Tricyclic compound or salts thereof, method for producing the same and antimicrobial agent containing the same

ABSTRACT

A tricyclic compound represented by the general formula (1) and salts thereof. &lt;CHEM&gt; A method for producing the tricyclic compound and salts thereof, and an antimicrobial agent containing the tricyclic compound and salts thereof as an active ingredient are also disclosed.

BACKGROUND OF THE INVENTION

i) Field of the Invention

The present invention relates to a novel tricyclic compound having anexcellent antimicrobial activity and oral absorbability and saltsthereof, a method for producing the same and an antimicrobial agentcontaining the same.

ii) Description of the Background Art

Conventionally, in compounds including a pyridonecarboxylic acid as abasic skeleton, many compounds having an excellent antimicrobialactivity and a wide antimicrobial spectrum are known as a usefulsynthetic antimicrobial drug or agent. For instance, norfloxacin (seeJapanese Patent Laid-open (Kokai) No. 53-141286), enoxacin (see JapanesePatent Laid-open (Kokai) No. 55-31042), ofloxacin (see Japanese PatentLaid-open (Kokai) No. 57-46986), ciprofloxacin (see Japanese PatentLaid-open (Kokai) No. 58- 76667) and the like are widely used as aninfective disease remedy in clinical medicine.

However, these compounds are still insufficient in antimicrobialactivity, enteron absorbability, metabolic stability, side-effects andthe like, and hence a novel compound satisfying these requirements hasbeen demanded.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide a noveltricyclic compound in view of the aforementioned drawbacks of the priorart, which possesses excellent antimicrobial activity and oralabsorbability.

It is another object of the present invention to provide a method forproducing a tricyclic compound having excellent antimicrobial activityand oral absorbability.

It is a further object of the present invention to provide anantimicrobial agent containing a novel tricyclic compound having anexcellent antimicrobial activity and oral absorbability.

In accordance with one aspect of the present invention, there isprovided a tricyclic compound represented by a general formula (1) andsalts thereof, ##STR2## wherein R¹ is one of a hydrogen atom and acarboxyl protecting group; wherein R² is one of a hydrogen atom, ahalogen atom, an amino group and a protected amino group; wherein R³ isone of a hydrogen atom and a lower alkyl group; wherein R⁴ is one of ahydrogen atom, a substituted or unsubstituted lower alkyl group, an acylgroup and an aralkyl group; wherein X is one of a hydrogen atom and ahalogen atom; wherein Y is one of a halogen atom, an amino group, ahydroxyl group, a cyclo-lower alkylamino group, a mono- or di- loweralkylamino group, a substituted or unsubstituted cyclic amino group, asubstituted or unsubstituted lower alkyl group, a substituted orunsubstituted cyclo- lower alkenyl group, a group represented by aformula R⁵ --(CH₂)m--A-- wherein R⁵ is one of a hydrogen atom, asubstituted or unsubstituted amino group, a substituted or unsubstitutedsaturated heterocyclic group having a nitrogen atom and a substituted orunsubstituted lower cycloalkyl group, wherein A is one of an oxygen atomand a sulfur atom, and wherein m is an integer of 0 to 3, and a grouprepresented by a formula R⁶ --SO₂ O-- wherein R⁶ is a lower alkyl group,a halo-lower alkyl group, a phenyl group or a mono-, di- ortri-substituted phenyl group by a lower alkyl group; and wherein n is aninteger of 0 to 2.

In accordance with another aspect of the present invention, there isprovided a method for producing a tricyclic compound represented by thefollowing general formula and salts thereof, ##STR3## wherein R^(1b) isone of a hydrogen atom and a lower alkyl group; wherein R² is one of ahydrogen atom, a halogen atom, an amino group and a protected aminogroup; wherein R³ is one of a hydrogen atom and a lower alkyl group;wherein R⁴ is one of a hydrogen atom, a substituted or unsubstitutedlower alkyl group, an acyl group and aralkyl group; wherein X is one ofa hydrogen atom and a halogen atom; wherein Y¹ is a halogen atom and agroup represented by a formula R⁶ --SO₂ O-- wherein R⁶ is a lower alkylgroup, a halo-lower alkyl group, a phenyl group or a mono-, di- ortri-substituted phenyl group by a lower alkyl group, and wherein n is aninteger of 0 to 2, comprising the steps of:

carrying out a cyclization of the compound represented by the followinggeneral formula, ##STR4## wherein R^(1a) is a lower alkyl group; whereinZ² and Z³ are either same or different and are one of a hydrogen atom, asubstituted or unsubstituted lower alkyl group, an acyl group, anaralkyl group and an amino protecting group; and wherein R², R³, X, Y¹and n are the same as described above, to prepare the compoundrepresented by the following general formula, ##STR5## wherein R^(1a),R², R³, X, Y¹, Z² and n are the same as described above;

and optionally followed by carrying out either an N-alkylation,N-acylation or N-aralkylation of the ring nitrogen atom;

and/or optionally followed by eliminating ester residue of the compound.

In accordance with a further aspect of the present invention, there isprovided a method for producing a tricyclic compound represented by thefollowing general formula and salts thereof, ##STR6## wherein R^(1b) isone of a hydrogen atom and a lower alkyl group; wherein R² is one of ahydrogen atom, a halogen atom, an amino group and a protected aminogroup; wherein R³ is one of a hydrogen atom and a lower alkyl group;wherein R⁴ is one of a hydrogen atom, a substituted or unsubstitutedlower alkyl group, an acyl group and an aralkl group; wherein X is oneof a hydrogen atom and a halogen atom; wherein Y² is one of an aminogroup, a cyclo- lower alkylamino group, a mono- or di- lower alkylaminogroup a substituted or unsubstituted cyclic amino group, a substitutedor unsubstituted lower alkyl group, a substituted or unsubstitutedcyclo- lower alkenyl group and a group represented by a formula R⁵--(CH₂)m--A-- wherein R⁵ is one of a hydrogen atom, a substituted orunsubstituted amino group, a substituted or unsubstituted saturatedheterocyclic group having a nitrogen atom and a substituted orunsubstituted lower cycloalkyl group, wherein A is one of an oxygen atomand a sulfur atom, and wherein m is an integer of 0 to 3, and wherein nis an integer of 0 to 2, comprising the steps of:

reacting the compound represented by the following general formula,##STR7## wherein Y¹ is a halogen atom or a group represented by aformula R⁶ --SO₂ O-- wherein R⁶ is a lower alkyl group, a halo-loweralkyl group, a phenyl group or a mono-, di- or tri-substituted phenylgroup by lower alkyl group; and wherein R^(1b), R², R³, R⁴, X and n arethe same as described above, with one of a compound represented by Y²--M wherein M is one of a hydrogen atom, an alkali metal atom and anorganometallic compound with the proviso that M is an organometalliccompound when Y² is a substituted or unsubstituted cyclo-lower alkenylgroup; and wherein Y² is the same as described above, salts or an alkalimetal alcoholate;

and optionally followed by eliminating ester residues of the objectcompound.

In accordance with still another aspect of the present invention, thereis provided a method for producing a tricyclic compound represented bythe following general formula and salts thereof, ##STR8## wherein R^(1c)is a carboxyl protecting group; wherein R² is one of a hydrogen atom, ahalogen atom, an amino group and a protected amino group; wherein R³ isa hydrogen atom or a lower alkyl group; wherein R⁴ is one of a hydrogenatom, a substituted or unsubstituted lower alkyl group, an acyl groupand an aralkyl group; wherein X is one of a hydrogen atom and a halogenatom; wherein Y is one of a halogen atom, an amino group, a hydroxylgroup, a cyclo- lower alkylamino group, a mono- or di- lower alkylaminogroup, a substituted or unsubstituted cyclic amino group, a substitutedor unsubstituted lower alkyl group, a substituted or unsubstitutedcyclo- lower alkenyl group, a group represented by a formula R⁵--(CH₂)m--A-- wherein R⁵ is one of a hydrogen atom, a substituted orunsubstituted amino group, a substituted or unsubstituted saturatedheterocyclic group having a nitrogen atom and a substituted orunsubstituted lower cycloalkyl group, wherein A is one of an oxygen atomand a sulfur atom, and wherein m is an integer of 0 to 3, and a grouprepresented by a formula R⁶ --SO₂ O-- wherein R⁶ a lower alkyl group, ahalo-lower alkyl group, a phenyl group and a mono-, di- ortri-substituted phenyl group by a lower alkyl group, and wherein n is aninteger of 0 to 2, comprising the step of:

reacting the compound represented by the following general formulawherein R², R³, R⁴, X, Y and n are the same as described above, ##STR9##with one of a compound represented by R^(1c) --X¹ wherein X¹ is one of ahydroxyl group and a halogen atom; and wherein R^(1c) is the same asdescribed above.

In accordance with still another aspect of the present invention, thereis provided an antimicrobial containing a tricyclic compound representedby general formula (1) and salts thereof as an active ingredient.

These and other objects, features and advantages of the presentinvention will be more fully appeared from the following description ofthe preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The present invention will now be described in detail with reference toExamples thereof.

Researches for providing clinically excellent synthetic antimicrobialdrugs or agents with improved antimicrobial activity, enteronabsorbability, metabolic stability, side-effects and the like have beencarried out. It has been found that a compound having a 1, 8-bridgedquinolone carboxylic acid structure represented by the general formula(1) exhibited an excellent antimicrobial activity against gram-negativesand gram-positives and satisfied the above requirements to be useful fora synthetic antimicrobial drug or agent. This finding has led to thecompletion of the present invention. General formula (1) is shown asfollows: ##STR10## wherein R¹ is a hydrogen atom or a carboxylprotecting group, wherein R² is a hydrogen atom, a halogen atom, anamino group or a protected amino group, wherein R³ is a hydrogen atom ora lower alkyl group, wherein R⁴ is a hydrogen atom, a substituted orunsubstituted lower alkyl group, an acyl group or an aralkyl group,wherein X is a hydrogen atom or a halogen atom, wherein Y is a halogenatom, an amino group, a hydroxyl group, a cyclo- lower alkylamino group,a mono- or di- lower alkylamino group, a substituted or unsubstitutedcyclic amino group, a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cyclo- lower alkenyl group, a grouprepresented by a formula R⁵ --(CH₂)m--A-- wherein R⁵ is a hydrogen atom,a substituted or unsubstituted amino group, a substituted orunsubstituted saturated heterocyclic group having a nitrogen atom or asubstituted or unsubstituted lower cycloalkyl group, A is an oxygen atomor sulfur atom, and m is an integer of 0 to 3, and a group representedby a formula R⁶ --SO₂ O-- wherein R⁶ is a lower alkyl group, ahalo-lower alkyl group, a phenyl group or a mono-, di- ortri-substituted phenyl group by a lower alkyl group, and wherein n is aninteger of 0 to 2.

Hence, according to the present invention, there are provided atricyclic compound represented by the general formula (1) or a saltthereof, a method for producing the tricyclic compound represented bythe general formula (1) or the salt thereof, and an antimicrobial agentcontaining the tricyclic compound represented by the general formula (1)or the salt thereof as an active ingredient.

According to the present invention, the term "lower" of a substituent ingeneral formula (1) means a group having 1 to 7 carbon atoms, preferably1 to 5 carbon atoms when the substituent is a straight or branched chaingroup or a group having 3 to 7 carbon atoms when the substituent is acyclic group.

The carboxyl protecting group represented by R¹ means any ester residueof a carboxylate which is readily cleaved to produce a correspondingcarboxyl group. As examples of this, for instance, lower alkyl groupssuch as methyl group, ethyl group, n-propyl group, t-butyl group and thelike, aralkyl groups such as benzyl group and the like, and aryl groupssuch as phenyl group and the like, which can be readily released bytreating under a moderate condition in a hydrolysis, a catalyticreduction or the like; or lower alkanoyloxy- lower alkyl groups such asacetoxymethyl group, pivaloyloxymethyl group and the like, loweralkoxycarbonyloxy- lower alkyl groups such as methoxycarbonyloxymethylgroup, 1-ethoxycarbonyloxyethyl group and the like, lower alkoxymethylgroups such as methoxymethyl group and the like, lactonyl groups such asphthalidyl group and the like, di- lower alkylamino- lower alkyl groupssuch as 1-dimethylaminoethyl group and the like, and(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl group, which can be readilyreleased in vivo can be given.

As to the halogen atom represented by R², fluorine atom, chlorine atom,bromine atom and the like are given, and fluorine atom is preferable.

Appropriate groups for protecting an amino group to provide a protectedamino group represented by R² include lower alkanoyl groups such asformyl group, acetyl group, propionyl group, hexanoyl group and thelike; mono-, di- or tri- halo(lower) alkanoyl groups such aschloroacetyl group, bromoacetyl group, dichloroacetyl group,trifluoroacetyl group and the like; lower alkoxy-carbonyl groups such aspropoxycarbonyl group, t-butoxycarbonyl group, t-pentyloxycarbonylgroup, hexyloxycarbonyl group and the like; carbamoyl groups; aroylgroups such as benzoyl group, toluoyl group, naphthoyl group and thelike; ar(lower)alkanoyl groups such as phenylacetyl group,phenylpropinoyl group and the like; aryloxycarbonyl groups such asphenoxycarbonyl group, naphthyloxycarbonyl group and the like;aryloxy(lower)alkanoyl groups such as phenoxyacetyl group,phenoxypropiony group and the like; arylglyoxyloyl groups such asphenylglyoxyloyl group, naththylglyoxyloyl group and the like;ar(lower)alkoxy-carbonyl groups substituted or unsubstituted with aproper substituent such as benzyloxycarbonyl group,phenethyloxy-carbonyl group, p-nitrobenzyloxycarbonyl group, and thelike; substituted or unsubstituted ar(lower)-alkylidene groups such asbenzylidene group, hydroxy-benzylidene group and the like;ar(lower)alkyl groups such as mono- (or di- or tri-) phenyl(lower)alkylgroup, for example, benzyl group, 1-phenylethyl group, benzhydryl group,trityl group or the like, and the like.

As regards the lower alkyl group represented by R³, for example, methylgroup, ethyl group and the like are given.

Regarding the substituted or unsubstituted lower alkyl group representedby R⁴, for instance, in addition to lower alkyl groups such as methylgroup, ethyl group, isopropyl group, t-butyl group, t-pentyl group orthe like, lower alkyl groups substituted with a hydroxyl group, ahalogen atom or a lower alkoxy group such as hydroxymethyl group,fluoromethyl group, methoxymethyl group or the like are given.

Relating to the acyl group represented by R⁴, for example, loweralkanoyl groups such as formyl group, acetyl group and the like, loweralkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonylgroup and the like, and aromatic acyl groups such as benzoyl group,phenoxycarbonyl group and the like are given.

As examples of the aralkyl group represented by R⁴, benzyl group,1-phenylethyl group and the like are given.

As examples of the halogen atom represented by X, fluorine atom,chlorine atom, bromine atom and the like are given, and fluorine atom ispreferable.

As regards the halogen atom represented by Y, the same atoms as those ofX are given, and fluorine atom and chlorine atom are preferable. As tothe cyclo- lower alkylamino group represented by Y, for instance,cyclopropylamino group, cyclobutylamino group and the like are given.Regarding the mono- or di- lower alkylamino group represented by Y, forexample, methylamino group, dimetylamino group, benzylamino group andthe like are given.

Further, as to the substituted or unsubstituted cyclic amino grouprepresented by Y, either saturated cyclic amino groups or unsaturatedcyclic amino groups can be used, and these groups may further includeone or more hetero atoms such as nitrogen atoms, oxygen atoms, sulfuratoms and carbonyl carbons and may further have either a mono-, di- ortri-cyclic structure. Such cyclic amino groups are given as thefollowing formulae (a')-(t). ##STR11## In these groups, B is an oxygenatom, a sulfur atom, --NR¹⁰ or --CONR¹⁰ wherein R¹⁰ is a hydrogen atom,a hydroxyl group, a lower alkyl group, a cyclo- lower alkyl group, anaralkyl group, an alkenyl group, an acyl group or a hydroxy- lower alkylgroup, D is CH or N, e is 3, 4 or 5, f is 1, 2 or 3, g is 0, 1 or 2, his 3 or 4, i is 1 or 2.

The suitable substituent for these cyclic amino group includes a loweralkyl group, a lower alkenyl group, a lower aralkyl group, an arylgroup, a hydroxyl group, a hydroxylower alkyl group, a substituted orunsubstituted amino group, a substituted or unsubstituted amino- loweralkyl group, a cyclic amino group as described above, an alkoxy group,an alkoxy- lower alkyl group, a halogen atom, a halo-lower alkyl group,an acyloxy group, an acyloxy- lower alkyl group, an acyl group, acarboxyl group, a carboxy- lower alkyl group, an alkoxycarbonyl- loweralkyl group, a mercapto group, a lower alkylthio group, a cyano group, anitro group and the like.

For example, there are given methyl group, ethyl group, n-propyl groupor the like for the lower alkyl group; vinyl group, allyl group or thelike for the lower alkenyl group; benzyl group, 1-phenetyl group or thelike for the lower aralkyl group; phenyl group or the like for the arylgroup; hydroxymethyl group, hydroxyethyl group hydroxypropyl group orthe like for the hydroxy- lower alkyl group; aminomethyl group,1-aminoethyl group, 2-amino-ethyl group, 1-amino-1-methylethyl group orthe like for the amino- lower alkyl group; methoxy group, ethoxy group,n-propoxy group or the like for the alkoxy group; methoxymethyl group,ethoxymethyl group or the like for the alkoxy- lower alkyl group;fluorine atom, chlorine atom, bromine atom or the like for the halogenatom; fluoromethyl group, trifluoromethyl group or the like for thehalo- lower alkyl group; acetoxy group, benzoyloxy group or the like forthe acyloxy group; acetoxymethyl group, benzoyloxy-methyl group or thelike for the acyloxy- lower alkyl group; a group exemplified above in R⁴or the like for the acyl group; carboxymethyl group, carboxyethyl groupor the like for the carboxy- lower alkyl group; methoxycarbonylmethylgroup, t-butoxycarbonylmetyl group or the like for the alkoxy-carbonyl-lower alkyl group; and methylthio group, ethylthio group or the like forthe lower alkylthio group.

In the above-described, regarding the substituent of the substitutedamino group and the substituted amino- lower alkyl group, for example,lower alkyl groups such as methyl group, ethyl group and the like, lowercycloalkyl groups such as cyclopropyl group, cyclobutyl group,cyclopentyl group and the like, lower alkenyl groups such as vinylgroup, allyl group and the like, lower aralkyl groups such as benzylgroup, 1-phenylethyl group and the like, aryl groups such as phenylgroup and the like, acyl groups such as groups exemplified above in R⁴and the like, amino acid or peptide residues such as glycyl-, leucyl-,valyl-, alanyl-, phenylalanyl-, alanyl-alanyl-, glycyl-valyl andglycyl-glycyl-valyl- groups and the like, amino acid residues or peptideresidues such as the above-described groups protected by a protectinggroup such as acyl group, aralkyl group or the like commonly used in thepeptide chemistry, and cyclic amino groups are given. The same ordifferent kinds of 1 to 2 substituents can be freely selected.

Relating to the compounds protected by such amino acid residues orpeptide residues, improvement of the water-solubility is expected.

As preferable examples of the substituted amino group and thesubstituted amino- lower alkyl group, in particular, methylamino group,ethylamino group, dimethylamino group, methylaminomethyl group,ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group,leucyl-amino group, valyl-amino group, alanyl-amino group,alanyl-alanyl-amino group and the like are given.

In R¹⁰, for instance, there are given methyl group, ethyl group or thelike for the lower alkyl group; cyclopropyl group, cyclobutyl group orthe like for the cyclo-lower alkyl group; benzyl group, 1-pyenylethylgroup or the like for the aralkyl group; vinyl group, allyl group or thelike for the alkenyl group; formyl group, acetyl group, methoxy-carbonylgroup or the like for the acyl group; and hydroxy-methyl group,hydroxyethyl group or the like for the hydroxy- lower alkyl group. Morepreferable examples of cyclic amino group are given by the followingformulae; ##STR12## wherein B is one of an oxygen atom, a sulfur atom,--NR¹⁰ and --CONR¹⁰ wherein R¹⁰ is one of a hydrogen atom, a hydroxylgroup, a lower alkyl group, a cyclo- lower alkyl group, an aralkylgroup, an alkenyl group, an acyl group and a hydroxy- lower alkyl group;wherein R⁷, R⁸ an R⁹ are either same or different and are one of ahydrogen atom, a lower alkyl group, a lower alkenyl group, a loweraralkyl group, an aryl group, a hydroxyl group, a hydroxy- lower alkylgroup, a substituted or unsubstituted amino group, a substituted orunsubstituted amino- lower alkyl group, a pyrrolidinyl group, apiperidino group, an azetidinyl group, an alkoxyl group an alkoxy- loweralkyl group, a halogen atom, a halo- lower alkyl group, an acyloxygroup, an acyloxy- lower alkyl group, an acyl group, a carboxyl group, acarboxy- lower alkyl group, an alkoxycarbonyl-lower alkyl group, amercapto group, a lower alkylthio group, a cyano group and a nitrogroup; wherein e is an integer of 3 to 5; wherein f is an integer of 1to 3; and wherein g is an integer of 0, 1 and 2.

The cyclic amino group represented by the formulae (a) and (a') could beexemplified azetidinyl group, pyrrolidinyl group or piperidino group,and the cyclic amino group represented by the formulae (b) and (b')could be exemplified piperazinyl group, homopiperazinyl group,morpholino group, thiomorpholino group,2,5-diazabicyclo[2.2.1]heptan-2-yl group,3,8-diazabicyclo[3.2.1]octan-8-yl group and the like.

Further preferable examples of groups represented by formulae (a), (a'),(b) and (b') are as follows:

3-hydroxyazetidinyl group, 3-aminoazetidinyl group,3-(N-t-butoxycarbonylamino)azetidinyl group, 3-acetylaminoazetidinylgroup, 3-methylaminoazetidinyl group, 3-dimethylaminoazetidinyl group,3-methylazetidinyl group, 3-amino-2-methylazetidinyl group; pyrrolidinylgroup, 3-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group,3-methoxypyrrolidinyl group, 3-methylpyrrolidinyl group,3-hydroxy-4-methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group,3-methylaminopyrrolidinyl group, 3-dimethylaminopyrrolidinyl group,3-acetylamino-pyrrolidinyl group, 3-t-butoxycarbonylaminopyrrolidinylgroup, 3-(N-acetyl)methylaminopyrrolidinyl group,3-(t-butoxycarbonyl)methylaminopyrrolidinyl group,3-aminomethylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group,3-dimethylaminomethylpyrrolidinyl group;

3-ethylaminomethylpyrrolidinyl group, 3-diethylaminomethylpyrrolidinylgroup, 3-(N-acetyl)aminomethylpyrrolidinyl group,3-(t-butoxycarbonyl)aminomethylpyrrolidinyl group,3-(N-acetyl)methylaminomethylpyrrolidinyl group,3-(t-butoxycarbonyl)methylaminomethylpyrrolidinyl group,3-(1-aminoethyl)pyrrolidinyl group, 3-(2-aminoethyl)pyrrolidinyl group,3-(1-amino-1-methylethyl)pyrrolidinyl group,3-(1-methylaminoethyl)pyrrolidinyl group,3-(1-dimethylaminoethyl)pyrrolidinyl group;

3-amino-4-methylpyrrolidinyl group, 3-amino-5-methylpyrrolidinyl group,3-methylamino-4-methylpyrrolidinyl group,3-dimethylamino-4-methylpyrrolidinyl group,3-ethylamino-4-methylpyrrolidinyl group,3-diethylamino-3-methylpyrrolidinyl group,3-diethylamino-4-methylpyrrolidinyl group,3-aminomethyl-4-methylpyrrolidinyl group,3-methylaminomethyl-4-methylpyrrolidinyl group;

3-dimethylaminomethyl-4-methylpyrrolidinyl group,3-ethylaminomethyl-4-methylpyrrolidinyl group,3-(1-aminoethyl)-4-methylpyrrolidinyl group,3-(2-aminoethyl)-4-methylpyrrolidinyl group, 3-amino-4-ethylpyrrolidinylgroup, 3-methylamino-4-ethylpyrrolidinyl group,3-dimethylamino-4-ethylpyrrolidinyl group,3-ethylamino-4-ethylpyrrolidinyl group,3-diethylamino-4-ethylpyrrolidinyl group,3-aminomethyl-4-ethylpyrrolidinyl group,3-dimethylaminomethyl-4-ethylpyrrolidinyl group;

3-amino-3-methylpyrrolidinyl group, 3-methylamino-3-methylpyrrolidinylgroup, 3-dimethylamino-3-methylpyrrolidinyl group,3-amino-3,4-dimethylpyrrolidinyl group, 3-amino-4,4-dimethylpyrrolidinylgroup, 3-amino-4,5-dimethylpyrrolidinyl group,3-amino-2,4-dimethylpyrrolidinyl group,3-methylamino-3,4-dimethylpyrrolidinyl group;

2-methyl-3-aminopyrrolidinyl group, 2-methyl-3-dimethylaminopyrrolidinylgroup, 3-amino-4-vinylpyrrolidinyl group, 3-amino-4-methoxypyrrolidinylgroup, 3-amino-4-methoxymethylpyrrolidinyl group,3-methylamino-4-methoxypyrrolidinyl group,3-dimethylamino-4-methoxypyrrolidinyl group,3-ethylamino-4-methoxypyrrolidinyl group,3-diethylamino-4-methoxypyrrolidinyl group;

3-benzylamino-4-methoxypyrrolidinyl group,3-aminomethyl-4-methoxypyrrolidinyl group,3-methylamino-4-methoxypyrrolidinyl group,3-dimethylaminomethyl-4-methoxypyrrolidinyl group,3-ethylaminomethyl-4-methoxypyrrolidinyl group,3-aminomethyl-3-methoxypyrrolidinyl group,3-methylaminomethyl-3-methoxypyrrolidinyl group,3-dimethylaminomethyl-3-methoxypyrrolidinyl group,3-amino-4-ethoxypyrrolidinyl group, 3-methylamino-4-ethoxypyrrolidinylgroup, 3-dimethylamino-4-ethoxypyrrolidinyl group,3-methylamino-4-ethoxypyrrolidinyl group,3-aminomethyl-4-ethoxypyrrolidinyl group,3-dimethylaminomethyl-4-ethoxypyrrolidinyl group,3-amino-4-carbamoylpyrrolidinyl group,3-amino-4-dimethylcarbamoylpyrrolidinyl group,3-amino-4-hydroxypyrrolidinyl group, 3-amino-4-hydroxymethylpyrrolidinylgroup, 3-amino-4-hydroxyethylpyrrolidinyl group;

3-amino-4-methyl-4-hydroxymethylpyrrolidinyl group,3-aminomethyl-4-hydroxypyrrolidinyl group,3-dimethylaminomethyl-4-hydroxypyrrolidinyl group,3,4-dihydroxypyrrolidinyl group, 3,4-dimethoxypyrrolidinyl group,3-hydroxy-4-methylpyrrolidinyl group, 3-amino-4-fluoropyrrolidinylgroup, 3-amino-4-fluoromethylpyrrolidinyl group,3-amino-4-trifluoromethylpyrrolidinyl group,3-methylamino-4-fluoropyrrolidinyl group,3-dimethylamino-4-fluoropyrrolidinyl group,3-aminomethyl-4-fluoropyrrolidinyl group,3-methylaminomethyl-4-fluoropyrrolidinyl group,3-dimethylaminomethyl-4-fluoropyrrolidinyl group;

3-methylamino-4-chloropyrrolidinyl group,3-aminomethyl-4-chloropyrrolidinyl group,3-methylaminomethyl-4-chloropyrrolidinyl group,3-(2-hydroxyethyl)aminomethylpyrrolidinyl group,3-(2-fluoroethyl)aminomethylpyrrolidinyl group,3-amino-4-methylthiopyrrolidinyl group,3-amino-4-methylsulfonylpyrrolidinyl group,3-formimidoylaminopyrrolidinyl group,3-(2-dimethylhydrazino)pyrrolidinyl group,3-amino-4-methylenepyrrolidinyl group,3-(t-butoxycarbonylaminoacetyl)amino-4-methylpyrrolidinyl group,3-aminoacetylamino-4-methylpyrrolidinyl group,3-(2-aminopropanoyl)amino-4-methylpyrrolidinyl group,3-(2-amino-3-phenylpropanoyl)amino-4-methylpyrrolidinyl group,3-(2-benzyloxycarbonyl)amino-3-methylbutanoyl-4-methylpyrrolidinylgroup, 3-(2-amino-3-methylbutanoyl)amino-4-methylpyrrolidinyl group,3-(2-amino-2-methylpropanoyl)amino-4-methylpyrrolidinyt group,7-amino-5-azaspiro[2,4]heptan-5-yl group;

piperazinyl group, 4-methylpiperazinyl group, 3-methylpiperazinyl group,2-methylpiperazinyl group, 3,4-dimethylpiperazinyl group,3,5-dimethylpiperazinyl group, 3,3-dimethylpiperazinyl group,3,4,5-trimethylpiperazinyl group, 4-ethoxycarbonylpiperazinyl group,4-t-butoxycarbonylpiperazinyl group, 4-acetylpiperazinyl group,4-benzyloxycarbonylpiperazinyl group, 4-ethylpiperazinyl group,3,4-diethylpiperazinyl group, 3,4,5-triethylpiperazinyl group,4-ethyl-3,5-dimethylpiperazinyl group, 3-methyl-4-acetylpiperazinylgroup, 3-methyl-4-t-butoxycarbonylpiperazinyl group, 4-benzylpiperazinylgroup, 4-n-propylpiperazinyl group;

4-isopropylpiperazinyl group, 4-t-butylpiperazinyl group,4-cyclopropylpiperazinyl group, 4-cyclopentylpiperazinyl group,4-cyclopropylmethylpiperazinyl group, 4-phenylpiperazinyl group,4-(p-dimethylaminophenyl)piperazinyl group,4-(p-methoxyphenyl)piperazinyl group, 4-(p-fluorophenyl)piperazinylgroup, 3-phenylpiperazinyl group, 3-(p-fluorophenyl)piperazinyl group,3-(p-chlorophenyl)piperazinyl group, 3-(p-hydroxyphenyl)piperazinylgroup, 3-(p-methylphenyl)piperazinyl group, 4-hydroxyethylpiperazinylgroup;

4-aminoethylpiperazinyl group, 4-allylpiperazinyl group,4-cinnamylpiperazinyl group, 4-cyanoethylpiperazinyl group,4-carboxyethylpiperazinyl group, 4-carboxymethylpiperazinyl group,4-(1,2-dicarboxyethyl)piperazinyl group, 4-hydroxypiperazinyl group,3-fluoromethyl-piperazinyl group, 3-trifluoromethylpiperazinyl group,4-formimidoylpiperazinyl group, 4-acetoimidoylpiperazinyl group;piperidino group, 4-aminopiperidino group, 4-dimethylaminopiperidinogroup, 4-hydroxypiperidino group, morpholino group,2-aminomethylmorpholino group, 2-methylaminomorpholino group,2-dimethylaminomorpholino group, thiomorpholino group, homopiperazinylgroup, 4-methylhomopiperazinyl group, thiazolidinyl group, andoxazolidinyl group.

In case that Y is the group represented by the formula R⁵ --(CH₂)m--A--,as regards substituents capable of substituting this group in which R⁵is an amino group, a saturated heterocyclic group having a nitrogen atomor a lower cycloalkyl group, the same groups as those capable ofsubstituting the substituted or unsubstituted cyclic amino groupdescribed above can be given. Further, as to the lower cycloalkyl group,cyclopropyl group, cyclobutyl group and the like are given. Regardingthe saturated heterocyclic group having a nitrogen atom, a 4 to 9membered ring is preferable, and the same saturated heterocyclic groupsas those exemplified for the above-described cyclic amino groups can begiven. For instance, azetidin-3-yl group, pyrrolidin-3-yl group and thelike are particularly preferable. Also, the connection between thesesaturated heterocyclic group and a group of --(CH₂)m--A-- can be carriedout on any atom of the ring.

In case that Y is the group represented by the formula R⁶ --SO₂ O--, inR⁶ there are given methyl group, ethyl group or the like for the loweralkyl group, fluoromethyl group, trifluoromethyl group or the like forthe halo- lower alkyl group, and para-methylphenyl group or the like forthe phenyl group mono-, di- or tri-substituted with a lower alkyl group.Further, as preferable examples of the group represented by R⁶ --SO₂O--, methanesulfonyloxy group, trifluoromethanesulfonyloxy group,para-toluene-sulfonyloxy group and the like are given.

As to the substituted or unsubstituted lower alkyl group represented byY, in addition to the lower alkyl groups such as methyl group, ethylgroup and the like, mono- or di-substituted, lower alkyl groupssubstituted by a carboxyl group, alkoxycarbonyl group, cyano group andthe like are given, and preferably carboxymethyl group,ethoxycarbonyl-(cyano)methyl group, t-butoxycarbonyl(eyano)methyl groupand the like are given.

As to the substituted or unsubstituted cyclo-lower alkenyl grouprepresented by Y, oxo-cyclohexenyl group, oxocyclopentenyl group and thelike are given, and preferably 3-oxo-1-cyclopentenyl group,3-oxo-1-cyclohexenyl group and the like are given.

Further, according to the present invention, the compound represented bygeneral formula (1) can be formed by both an salt with acid and a saltwith base, and these salts can include those forming a chelate salt withboron compound. As regards the salt with acid for example, (a) saltswith a mineral acid such as hydrochloric acid, sulfuric acid or thelike, (b) salts with an organic carboxylic acid such as formic acid,citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid,maleic acid or the like, and (c) salts with a sulfonic acid such asmethanesulfonic acid, benzene-sulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid or the like can begiven. Further, as to the salt with base, for instance, (a) salts withan alkali metal such as sodium, potassium or the like, (b) salts with analkaline earth metal such as calcium, magnesium or the like, (e)ammonium salt, and (d) salts with an organic base having a nitrogen atomsuch as trimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, cyclohexylamine, procaine, dibenzylamine,N-benzyl-g-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine orthe like can be given.

Further, as examples of boron compound, for instance, boron halide suchas boron fluoride and the like, lower acyloxy boron such as acetoxyboron and the like. According to the present invention, the compoundrepresented by general formula (1) exists not only in an unsolvated formbut also in a hydrate or solvated form and hence includes a crystaltype, a hydrate type and a solvated type.

Also, the compound represented by general formula (1) can include anasymmetric carbon atom and thus exists in the form of optically activesubstances. Of course, these optically active substances can be includedin the compound of the present invention. Further, the compoundrepresented by general formula (1) can include at least two asymmetriccarbon atoms and exist in the form of other stereo-isomers such as cisor trans forms. Of course, these stereoisomers can be included in thecompound of the present invention.

The compound represented by general formula (1) can be prepared bysuitable certain methods. The preferable preparation methods areexemplified as follows.

Process 1:

The compound is represented by general formula (1), wherein R¹ is ahydrogen atom or a lower alkyl group and Y is a halogen atom or a grouprepresented by a formula R⁶ -- SO₂ O-- wherein R⁶ is a lower alkylgroup, a halo- lower alkyl group, a phenyl group or a mono-, di- ortri-substituted phenyl group by a lower alkyl group, and this compoundwill be produced by a series of steps shown by reaction scheme (1) asfollows: ##STR13## In the above formula, Y¹ is a halogen atom or a grouprepresented by a formula R⁶ --SO₂ O-- wherein R⁶ is a lower alkyl group,a halo- lower alkyl group, a phenyl group or a mono-, di- ortri-substituted phenyl group by a lower alkyl group, Z¹ is a hydroxyprotecting group, Z² and Z³ are either same or different and are one ofa hydrogen atom, a lower alkyl group, an acyl group and an aminoprotecting group; R^(1a) is a lower alkyl group and R², R³, R⁴, X and nare the same as described above.

In this process, a starting material is an o-hydroxyalkyl-anilinederivative or o-(acyloxyalkyl)aniline derivative represented by generalformula (A) or (C). In this case, regarding a protecting group for ahydroxyl group represented by Z¹, any group usually used in protecting ahydroxyl group can be employed, for example, acyl group, trialkylsilylgroup, benzyl group, tetrahydropyranyl group and the like are given.Preferable examples of the acyl group include acetyl group, propionylgroup, benzoyl group and pivaloyl group. Preferable examples of thetrialkylsilyl group include t-butyldimethylsilyl group, triethylsilylgroup and t-butyldiphenylsilyl group.

In this process, firstly, compound (A) or compound (C) is reacted withdiethyl ethoxymethylene malonate to obtain compound (B) or compound (D),respectively. This reaction can be carried out at reaction temperaturesof 80° to 150° C. without using any solvent but can be performed using asolvent having no activated hydrogen such as toluene, xylene or thelike.

Compound (B) is converted into compound (D) by protecting a hydroxylgroup. In case that the protecting group is an acyl group, this reactioncan be carried out by any reaction usually used for acylation ofhydroxyl group. For instance, acylehloride corresponding to Z¹ andcompound (B) are reacted with each other in a solvent having noactivated hydrogen such as dichloromethane, ether or acetone at atemperature of 0° C. to room temperature in the presence or absence of abase such as pyridine, triethylamine, sodium carbonate or potassiumcarbonate.

In this case, regarding the acyl group represented by Z¹, any groupusually used in protecting a hydroxyl group for example, acetyl group,propionyl group, benzoyl group and the like can be used.

In case that the protecting group is a trialkylsilyl group, thisreaction can be carried out by any reaction usually used fortrialkylsilylation of hydroxyl group. For instance, trialkylsilylhalidecorresponding to Z¹ and compound (B) are reacted with each other in asolvent having no activated hydrogen such as dichloromethane,N,N-dimethylformamide or acetone at temperatures of 0° C. to 60° C. inthe presence of a base such as imidazole, triethylamine or 2,6-lutidine.

Compound (D) is cyclized to obtain compound (E). This reaction can becarried out by a variety of methods. For example, compound (D) is heatedin an inert solvent such as diphenyl ether or dibenzyl ether attemperatures of 180° to 270° C. or in polyphosphoric acid attemperatures of 100° to 160° C.

Compound (E) is converted into compound (F) by eliminating theprotecting group of hydroxyl group. In case that the protecting group isan acyl group, compound (E) is converted into compound (F) byalcoholysis. In this reaction, by using, as a solvent, an alcoholcorresponding to R^(1a) to be substituted to a carboxylic acid ofcompound (F) together with benzene, toluene, N,N-dimethylformamide,dimethylsulfoxide or N-methylpyrrolidone or without using any solventexcept the alcohol, and using a catalytic amount of sodium hydroxide,potassium hydroxide, sodium methylate, sodium ethylate or a base such asa metal alcoholate corresponding to R^(1a), compound (E) is reacted atroom temperature to a temperature of 100° C .

In case that the protecting group is a trialkylsilyl group, compound (E)is converted into compound (F) by acidic hydrolysis. In this reaction,by using tetrahydrofuran, alcohol, ether and the like, together with anacid such as acetic acid, hydrochloric acid, p-toluensulfonic acid andthe like in the presence or absence of water. Compound(E) is convertedinto compound (F) by fluoride-assisted reaction by usingtetrahydrofuran, together with tetra-n-butylammonium fluoride, compound(E) is reacted at a temperature of 0° C. to room temperature.

Compound (F) is reacted with an aminating agent such asmesitylenesulfonylhydroxyamine, o-(2,4-dinitrophenyl)hydroxylamine orthe like to obtain compound (G). This reaction is carried out in thepresence of a base such as sodium carbonate, potassium carbonate or thelike in a solvent such as N,N-dimethylformamide, N-methylpyrrolidone orthe like at a temperature of 0° to 60° C.

Compound (G) is cyclized to obtain compound (H). This cyclizationreaction is carried out by a variety of methods. For instance, compound(G) is reacted with triphenylphosphine and diethyl azodicarboxylate in asolvent such as tetrahydrofuran at a temperature of 0° to 60 ° C.

Further, this cyclization reaction could be carried out aftersubstitution on the amino group by a lower alkyl group and anamino-protection group such as Z² or Z³, if desired. Wherein, loweralkyl group could be methyl, ethyl and so on, and amino-protecting groupcould be the exemplified ones for protection of R².

Compound (H) is alkylated or acylated to obtain compound (I), ifdesired. The alkylation is carried out by reacting compound (H) with analkylating agent such as dialkylsulfate, alkyl iodide, alkyl bromide orthe like corresponding to the desired alkyl group in a solvent such asN,N-dimethylformamide, N-methylpyrrolidone or the like at roomtemperature to a temperature of 150° C. preferably in the presence of abase such as sodium carbonate, potassium carbonate or the like.

The acylation can be carried out by any conventional method. Forinstance, acylchloride corresponding to the desired acyl group isreacted with compound (H) in a solvent such as dicholoromethane, etheror acetone at a temperature of 0° C. to room temperature in the presenceor absence of base such as pyridine, triethylamine, sodium carbonate,potassium carbonate or the like; and acid such as formic acid, aceticacid or the like, or acid anhydride from them are reacted with compound(H) at room temperature to 120° C.

Compound (I) is hydrolized to obtain compound (i). This reaction iscarried out by using a known reaction. For instance, compound (I) can bereacted in an aqueous alkaline solution such as aqueous sodium hydroxidesolution, aqueous potassium hydroxide solution or aqueous sodiumcarbonate solution, or in an aqueous acidic solution such ashydrochloric acid or acetic acid at room temperature to a temperature of100° C. by using a solvent mixible with water such as ethanol, methanol,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide or the like orwithout using any solvent.

Process 2:

The compound is represented by general formula (1), wherein R⁴ ishydrogen atom or a lower alkyl group, Y is an amino group, hydroxylgroup, a cyclo- lower alkylamino group, a mono- or di- lower alkylaminogroup, a substituted or unsubstituted cyclic amino group, a substitutedor unsubstituted lower alkyl group and a substituted or unsubstitutedcyclo- lower alkenyl group, a group represented by a formula R⁵--(CH₂)m--A-- wherein R⁵ is a hydrogen atom, a substituted orunsubstituted amino group, a substituted or unsubstituted saturatedheterocyclic group having a nitrogen atom or a substituted orunsubstituted lower cyclo-alkyl group, A is an oxygen atom or sulfuratom, and m is an integer of 0 to 3. This compound will be prepared inthe process shown by reaction scheme (2): ##STR14## In this scheme,R^(1b) is a hydrogen atom or a lower alkyl group, Y² is an amino group,a cyclo- lower alkylamino group, a mono- or di- lower alkylamino group,a substituted or unsubstituted cyclic amino group, a substituted orunsubstituted lower alkyl group and a substituted or unsubstitutedcyclo- lower alkenyl group or a group represented by a formula R⁵--(CH₂)m--A-- wherein R⁵ is a hydrogen atom, a substituted orunsubstituted amino group, a substituted or unsubstituted saturatedheterocyclic group having nitrogen atom or a substituted orunsubstituted lower cyclo-alkyl group, A is an oxygen atom or sulfuratom, and m is an integer of 0 to 3, and wherein M is a hydrogen atom,an alkali metal atom or an organo- metallic compound with the provisothat M is an organo- metallic compound when Y² is a substituted orunsubstituted cyclo-lower alkenyl group, and R², R³, R⁴, X, Y¹ and n arethe same as described above.

That is, the compound is obtained by reacting compound (K) obtained inprocess 1 with a compound represented by a formula Y² --M or its salt oran alkali metal alcoholate.

This reaction is preferably carried out in an inert reaction solventsuch as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide,sulfolane, N-methylpyrrolidone or the like or a mixture thereof.Further, this reaction can be carried out in the form of a chelatecompound of (K) resulted from a reaction of boron trifluoride or itssolvated complex or tris(lower acyloxy) borane in an inert solvent. Thereaction temperature is preferably 50° to 200° C. , and 80° to 150° C.is more preferable. This reaction is preferably carried out in thepresence of a base such as triethylamine, 2,6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, analkali metal carbonate or the like for neutralizing a hydrogen halidewhich is produced in this reaction. It can also be neutralized by usingan excess amount of an alkali metal alcoholate or amine. In case that Y²is a substituted or unsubstituted cyclo-lower alkenyl group, Mrepresents an organometallic compound which is, preferably, trialkyltin, such as tributyl tin.

This reaction could be preferably carried out using palladium catalystsuch as tetrakis (triphenyl phosphine) palladium,bis(acetonitrile)palladium (II) chloride,bis(triphenylphosphine)palladium (II) chloride and so on. In thisreaction, although a product may be obtained in a salt form, ifnecessary, the product can be treated by an acid such as acetic acid,trifluoroacetic acid, hydrochloric acid or the like or a base such assodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide or the like to convert into a free form.

In this reaction, when there are substituents such as hydroxyl group,mercapto group, carboxyl group and amino group in the compoundrepresented by Y² --M, there are some cases where the yield of thecompound (L) in the above reaction is remarkably dropped. In such acase, after hydroxyl group, mercapto group, carboxyl group and aminogroup in the compound represented by Y² --M are protected appropriately,the reaction is carried out in the process of reaction scheme (2), andthen the elimination of the protecting groups in the obtained compoundis carried out to bring about a excellent yield. In this case, any knownprotecting groups can be used, for example, acyl group, alkoxycarbonylgroup or benzyl group for hydroxyl group; acyl group or ethylthio groupfor mercapto group; benzyl group for carboxyl group; and acyl group,alkoxycarbonyl group, benzyl group or the like for amino group. Theseprotecting groups can be removed by a proper known method such as acidichydrolysis, basic hydrolysis, catalytic hydrogenation or the like.

Process 3:

The compound represented by the general formula (1), wherein R¹ is acarboxyl protecting group, is produced in the process shown by reactionscheme (3): ##STR15## In this scheme, R^(1c) is a carboxyl protectinggroup, X¹ is a hydroxyl group or a halogen atom, and R², R³, R⁴, X, Yand n are the same as described above.

That is, compound (M) is reacted with a halide represented by R^(1c)--X¹ to obtain compound (N).

This reaction is preferably carried out at room temperature to atemperature of 100° C. in the presence of bases such as triethylamine,trimethylamine, sodium hydroxide, potassium hydroxide, potassiumcarbonate, and the like by using an inert solvent such asN,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or thelike. In this process, there are also some cases where the yield of thecompound is dropped due to substituents of Y like process 2, but thisproblem can be solved in the same manner as described in process 2.

Although a producing method of a new tricyclic compound represented bygeneral formula (1) has herein been explained with reference toprocesses 1 to 3, the producing method of the compound according to thepresent invention is not restricted to these methods.

For example, a compound represented by general formula (1), wherein R³is a hydrogen atom and n=1, can be also prepared in processes 4 to 7shown by reaction scheme (4): ##STR16## In this formula, R^(2a) is ahydrogen atom or a halogen atom R¹¹ and R¹² are a hydrogen atom or acarboxyl protecting group, Z⁴ is a leaving group, and R⁴, X and Y¹ arethe same as described above.

Process 4:

Compound (P) or its salts can be prepared by the Michael additionreaction of compound (0) or its salts with a compound (Q) having aconjugated double bond.

As examples of preferable salts of compound (0) and compound (P), referto the examples of the compound represented by formula (1).

This reaction usually proceeds in the presence of a base or a Lewisacid. Preferable bases, include alkali metal hydrides such as sodiumhydride, potassium hydride and the like, alkaline earth metal hydridessuch as calcium hydride and the like, alkali metal alkoxides such aspottasium t-butoxide and the like, and potassium fluoride and the like.As examples of a preferable Lewis acid, zinc halides such as zincbromide, zinc chloride and the like, magnesium halides such as magnesiumbromide, magnesium chloride and the like, titanium compounds such astitanium tetrachloride, titanium tetraethoxide, titanium tetrapropoxideand the like, boron trifluoride and the like are given.

The reaction is usually carried out in a solvent, for example, water,alcohol such as methanol, ethanol or the like, methylene chloride,tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide,N-methylpyrrolidone or the like, or a mixture thereof, and the reactioncan be run in any solvent or mixed solvent as far as such a solvent ormixed solvent does not have any bad influence on the reaction.

As examples of an adjuvant on using the solvent or activity of a Lewisacid, a compound having an ether bonding modifying the activity of Lewisacid, for example, diethyl ether, 1,2-epoxypropane, tetra-hydrofuran,dioxane or the like can be used.

The reaction temperature is not limited in particular, but the reactionis usually carried out under heating.

Process 5:

Compound (R) or its salts can be made by ring-closure reaction ofcompound (P) or its salt.

As examples of a preferable salt of compound (R), refer to the examplesof the compound represented by formula (1).

As to the leaving group represented by Z⁴, for example, halogen atomssuch as fluorine or the like are given.

The ring-closure reaction is usually carried out in the presence of abase in a solvent. As examples of preferable base and solvent, refer tothe examples shown in process 4.

The reaction temperature is not limited in particular, but the reactionis usually carried out under heating.

Depending on the reaction condition such as using dimethylsulfoxide, thering-closure reaction in process 5 continuously occurs after the Michaeladdition reaction in process 4, and the reactions collectively carriedout in one pot.

Process 6:

Compound (S) or its salts can be formed by a solvolysis reaction ofcompound (R) or its salts.

As examples of a preferable salt of compound (S), refer to the examplesof compound represented by formula (1).

The solvolysis reaction is preferably carried out in the presence of abase or an acid including Lewis acid. Regarding a preferable base,inorganic bases and organic bases, for example, alkali metals such assodium, potassium and the like, alkaline earth metals or its hydroxides,carbonates or hydrogen carbonate such as magnesium, calcium and thelike, trialkylamines such as trimethylamine, triethylamine and the like,picoline, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene andthe like are given.

Preferable acids include organic acids such as formic acid, acetic acid,glacial acetic acid, propionic acid, trichloroacetic acid,trifluoroacetic acid and the like, and inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, hydrochloride,hydrobromide and the like.

The elimination using a Lewis acid typified by a trihaloacetic acid suchas trichloroacetic acid, trifluoroacetic acid or the like is preferablycarried out in the presence of a cation trapping agent such as anisole,phenol or the like.

The reaction is usually carried out in a solvent, for example, water,alcohol such as methanol, ethanol or the like, methylene chloride,tetrahydrofuran, N,N-dimetylformamide, dimethyl sulfoxide or the like,or a mixture thereof, and the reaction proceeds in any solvent or mixtedsolvent as far as such a solvent or mixted solvent does not have any badinfluence to the reaction. A liquid base or acid can also be used as asolvent.

The reaction temperature is not restricted in particular, but thereaction is usually carried out under cooling or heating.

Process 7:

Compound (I-(1)) or its salts can be formed by a decarboxylationreaction of compound (S) or its salts.

As examples of a preferable salt of compound (I-(1)), refer to theexamples of the compound represented by formula (1).

This reaction is carried out by heating under an inert gas such asnitrogen or according to a normal method such as reduction.

The reaction is usually carried out in a solvent, for example, water,alcohol such as methanol, ethanol or the like, methylene chloride,tetrahydrofuran, N,N-dimetylformamide, dimethyl sulfoxide or the like,or a mixture thereof, and the reaction proceeds in any solvent or mixtedsolvent as far as such a solvent or mixted solvent does not have any badinfluence on the reaction.

The reaction temperature is not restricted in particular, but thereaction is usually carried out under cooling or heating.

According to the method including above processes 4 to 7, compound(I-(1)) wherein R^(2a) is a halogen atom can be effectively obtained,which will herein after be referred to as compound(I-(2). This compound(I-(2)) can be readily modified to compound (1-(3)) having an aminogroup in processes 8 and 9 shown by reaction scheme (5): ##STR17## Inthis formula, R^(2b) is a halogen atom, R^(1a) is an amino protectinggroup, and R⁴, X and Y¹ are the same as described above.

Process 8:

Compound (T) or its salts can be formed by reacting compound (I-(2)) orits salts with an amine compound (U) or its salts.

As examples of a preferable salt of compound (T), refer to the examplesof the compound represented by formula (1).

Examples of the amino protecting group represented by R¹³ are the sameas those given for the protecting group in R². This reaction isgenerally carried out by using an equivalent or somewhat slightly excessamount of compound (U) or its salts to the amount of compound (I-(2)) orits salts in the presence of an acid acceptor such as sodium carbonate,calcium carbonate, sodium hydrogen carbonate, triethylamine,1,8-diazabicyclo[5.4.0]undee-7-ene or the like, and an excess amount ofcompound (U) may be used as the acid acceptor.

The reaction is usually carried out in a solvent, for example, anaromatic hydrocarbon such as benzene, toluene, xylene or the like, anether such as tetrahydrofuran, dioxane, monoglyme or the like, ahalogenated hydrocarbon such as methylene chloride, chloroform or thelike, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine orthe like, and the reaction can be carried out in any solvent or mixtedsolvent as far as such a solvent or mixted solvent does not have any badinfluence on the reaction.

The reaction temperature is not restricted in particular, but thereaction is usually carried out under heating.

Process 9:

Compound (I-(3)) or its salts can be formed by an deprotecting reactionof compound (T) or its salts to eliminate the amino protecting groupthereof.

As examples of a preferable salt of compound (I-(3)), refer to theexamples of the compound represented by formula (1).

For the deprotecting reaction of the amino protecting group, the usualreaction conditions for the hydrolysis or the catalytic reduction can beapplied.

More specifically, in case of the hydrolysis, the reaction is carriedout in the presence of a basic compound such as sodium hydroxide,potassium hydroxide, barium hydroxide, potassium carbonate or the like,a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid orthe like, or an organic acid such as acetic acid, aromatic sulfonic acidor the like in a solvent, for example, water an alcohol such asmethanol, ethanol, isopropanol or the like, a ketone such as acetone,methyl ethyl ketone or the like, an ether such as dioxane,ethyleneglycol, diethyl ether or the like, acetic acid or the like, or amixture thereof. The reaction is usually carried out at room temperatureto a temperature of 200° C., preferably room temperature to 120° C.

In case of the catalytic reduction, the reaction is usually carried outin the presence of a catalyst such as palladium on carbon, palladiumblack, platinum dioxide or the like in a solvent such as methanol,ethanol, propanol, acetic acid, tetrahydrofuran, dioxane, ethyl acetate,water or the like or a mixted solvent thereof at the atmosphericpressure to a pressure of 100 atm under hydrogen while stirring.

The reaction temperature is usually room temperature to 100° C. and isusually terminated in 1 to 48 hours.

In particular, in the group represented by Y, the substituents can bemutually converted by a variety of known methods. In process 2, althoughone example of the mutual conversion of the substituents is partlydescribed as addition and elimination of the protecting groups, otherreaction examples are described as follows. That is, a conversion fromhydroxyl group to a halogen atom; an acylation of hydroxyl group,mercapto group, and primary and secondary amino groups; a conversionfrom a halogen atom to an amino or cyano group; a removal ofalkoxycarbonyl group, benzyl group and acyl group; an alkylation of acarboxyl group, and primary and secondary amino groups; a conversionfrom an alkenyl group to alkyl group; and a cyclization by a connectionof two groups.

A producing method of the compound of the starting material (A) or (C)wherein n=0 in process 1, for example, is disclosed in Japanese PatentLaid-open (Kokai) No. Hei 2-157282. Further, the compound of thestarting material (A) or (C) wherein n=1 can be prepared by a processshown in reaction scheme (6) belows, and by a method described in "J.Heterocyclic. Chem., 25, 1567, 1988". More specifically, it can beprepared by the described method in a comparative example and equivalentmethods thereof. ##STR18## In this scheme, Z⁵ is a hydrogen atom or anacyl group, and R², X and Y¹ are the same as described above.

As preferable examples of protection of Z⁵, the same as described abovewith reference to Z¹ can be given.

The starting material (O) in process 4 can be prepared, for example, byreaction scheme (7): ##STR19## wherein R¹⁴ is a lower alkyl group, R¹⁵is a protected amino group, Z⁶ is a leaving group, and R¹, R^(2a), R⁴,X, Y¹ and Z⁴ are as defined before. Here, examples of the protectedamino group, represented by R¹⁵ are the same as those given for R¹³, andthe examples of Z⁶ are the same as those given for Z⁴.

Concerning reagents usable for synthesizing the starting material (O)and reaction conditions such as the selection of solvents andtemperature, the following preparation examples may be referred to. Thestarting material (O') is described in Japanese Patent Laid-Open (Kokai)No. SHO 59-212474 (corresponding to U.S. Pat. No. 4,556,658).

Further the substituents appeared in processes (1) to (7), having nodescription of their definitions can be referred to the abovedescription of the corresponding substituents in the compoundrepresented by general formula (1).

The effects and advantages of the present invention will now bedescribed in detail.

(1) Antimicrobial activity:

The minimum inhibitory concentration (MIC: μg/ml) of typical compoundsrepresented by general formula (1) of the present invention is measuredby the standard method of Japanese literature "Chemotherapy, Volume 29,No. 1, pp. 76- 79, 1981". The results are shown in Table 1 in whichcompound numbers are the same as those indicated in Examples.

                  TABLE 1                                                         ______________________________________                                                Minimum Inhibitory                                                            Concentration (μg/ml)                                                        E. coli NIH JC-2                                                                           S. aureus 209 p                                                                          P. aeruginosa                               Compound No.                                                                            (IFO* 12734) (IFO 12732)                                                                              (IFO 3445)                                  ______________________________________                                        30        0.025        0.1        0.2                                         73        0.1          0.78       0.78                                        ______________________________________                                         *Institute of Fermentation, Osaka                                        

(2) Absorption and excretion:

The absorbability and excretion after oral administration of thecompounds of the present invention were tested by measuring recovery inurine and in bile as follows.

(a) Recovery in urine:

To a group of three male JCL-SD rats (6 weeks old) fasted overnight, asubject compound was prepared to 20 mg/10 ml/kg with 0.5% ofmethylcellulose solution and was orally administrated. The sampling wascarried out by collecting urine in 0 to 6 hours and 6 to 24 hours. Theconcentration of the subject compound in the urine was examined by adisk method by using Bacillus subtills ATCC 6633 as a testing bacillusto obtain an excretion rate in urine for 24 hours.

(b) Recovery in bile:

A subject compound was prepared in the same manner as the recovery inurine and was orally administrated to the rats and bile was collected byusing a polyethylene tube inserted into the choledochus in 24 hours. Theconcentration of the subject compound in the bile sample was examined inthe same manner as the recovery in urine to obtain an excretion rate inbile for 24 hours.

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                       Excretion Rate                                                                (%, 24 hours)                                                  Compound No.     In Urine In Bile                                             ______________________________________                                        30               59.7     3.8                                                 ______________________________________                                    

As described above, according to the present invention, the compoundsrepresented by general formula (1) and salts thereof, which are novelcompounds, exhibit an extremely excellent antimicrobial activity againstgram-negative and gram-positive bacteria and possess a high oralabsorbability. When the compounds represented by general formula (1) ofthe present invention are used as antimicrobial agents, the compoundscan be treated as compositions together with pharmaceutical allowablecarriers for parenteral dosage such as injection, per rectum, eyeinstillation and the like and oral dosage in the form of solid andsolution.

Relating to the form of the composition for injections, pharmaceuticalallowable axenic water or nonaqueous solution, suspension or emulsion,and the like are given. As examples of appropriate nonaqueous carrier,diluent, solution or vehicle, propylene glycol, polyethylene glycol andvegetable oils such as olive oil and injectable organic estersincluding, for example, oleic ester are given. These compositions caninclude supplementary agents such as antiseptics, wetting agents,emulsifiers, dispersants and the like. These compositions, for example,can be sterilized by filtering with a bacteria holding filter or mixinga sterilizer in the form of an axenic solid composition soluble insterilized water or other several sterilizing injectable solutes ormedia right before the use.

The preparations for eye instillation dosage can preferably includedissolution adjuvants, preservatives, isotonic agents, mucilages and thelike.

The solid preparations for oral dosage can include capsules, tablets,pills, powders and granules. In preparing the solid preparations,generally, the compound of the present invention is mixed with at leastone kind of an inert diluent such as sucrose, lactose or starch. In ausual preparation, the preparations can further include a supplementarymaterial except the inert diluent, for example, a lubricant such asmagnesium stealate or the like. Further, the capsules, tablets and pillscan further include a buffer. The tablets and pills can further apply anenteric coat thereon.

The solution preparations for oral dosage can include inert diluentsusually used by a person skilled in the art, for instance,pharmaceutical allowable emulsifiers including water, solutions,suspensions, syrups and elixirs. In addition to such inert diluents, thecompositions can be blended with supplementary agents such as wettingagents, emulsifiers, suspensions, edulcorants, flavors and perfumes.

The preparations for per rectum dosage can preferably include excipientssuch as cocoa butter or suppository wax in addition to the compound ofthe present invention.

According to the present invention, the dose of the compound representedby general formula (1) depends on properties of the compound to bedosed, dosing route, the desired treating period and other factors, andis, in general, approximately 0.1 to 1000 mg/kg a day, and preferablyapproximately 1 to 100 mg/kg a day. If necessary, this dose for one daycan be separated into 2 to 4 times.

As described above, according to the present invention, the compoundsrepresented by general formula (1) and salts thereof are extremelyvaluable as antimicrobials and can be used as not only pharmaceuticalsor drugs for human body and animals but also drugs for fishes,agricultural chemicals and preservatives for foods. Further, thecompounds of this invention are expected to inhibit the growth of virusespecially HIV(human immuno deficiency virus) and the like.

EXAMPLES

Now, the present invention will be described in detail with reference tothe exemplary embodiments, and it should be understood that theseembodiments are given for only illustration of the invention and are notintended to be limitative therefor. Position numbers of two noveltricyclic compounds, represented by general formula (1) wherein n is 0and 1, of the present invention for use in Reference Examples andinventive examples are exemplified as follows. ##STR20##

REFERENCE EXAMPLE 1

2,3-Difluoro-6-nitrophenylacetic acid (1):

64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran, and,while the mixed solution was stirred and cooled on ice, a solutionobtained by dissolving 258 g of diethyl malonate in 400 ml oftetrahydrofuran was dropped to the mixed solution through 1 hour and 40minutes so that the reaction temperature was kept below 20° C. Then,while the reaction solution was stirred and cooled on ice, 200 ml oftetrahydrofuran solution dissolving 142 g of 2,3,4-trifluoronitrobenzenewas dropped to the reaction solution through 2 hours so that thereaction temperature was kept below 10° C. After reacting at roomtemperature for 2 hours, 100 ml of acetic acid was added to the reactionsolution and tetrahydrofuran was removed by distillation. To theresidue, 1 1 of chloroform, 1.5 1 of water and 100 ml of concentratedhydrochloric acid were added, and the solution was separated. Theorganic layer was separated from the solution, and the solvent wasremoved by distillation. To the residue, 250 ml of 4 N hydrochloric acidand 200 ml of acetic acid were added, and the solution was heated underreflux for 11 hours. After removing 150 ml of content solution bydistillation, 50 ml of acetic acid and 50 ml of water were added to thesolution, and the solution was heated under reflux for 31 hours. Afterthe solution was air-cooled, the precipitated crystal was filtered off,washed with diisopropyl ether and was dissolved in 400 ml of methanol.After treating with active carbon, the solvent was removed bydistillation. The precipitated crystal was dispersed in diisopropylether and was filtered off to obtain 100 g of the subject compound (1)in a 56% yield.

REFERENCE EXAMPLE 2

Diethyl {2-(2-Acetoxyethyl)-3,4-difluoroanilino}methylene malonate (2):

19.8 g of the sodium borohydride was added to 60 ml of tetrahydrofuran,and, while the mixed solution was cooled on ice below 10° C., a solutionobtained by dissolving 60 g (276 mmol) of2,3-difluoro-6-nitrophenylacetic acid in 20 ml of tetrahydrofuran wasdropped to the mixed solution through I hour. Then, 120 ml oftetrahydrofuran solution dissolving 90 ml of boron trifluoride ethylether complex was dropped to the reaction solution through 1 hour below10° C. The solution was stirred for 15 minutes under cooled on ice andfor 20 minutes at room temperature. To 1.5 1 of methylene chloride, 1.21 of ice/water, 84 g of sodium hydrogen carbonate was added, and, whilewell stirring this solution, the reaction solution was slowly added tothis solution. The obtained solution was stirred overnight. The organiclayer was separated from the solution, and after drying over magnesiumsulfate, solvent was removed by distillation to obtain 61 g of oily3,4-difluoro-2-(2-hydroxyethyl)nitrobenzene. To this oily material, 58ml (414 mmol) of triethylamine and 500 ml of methylene chloride wereadded, and while cooling on ice, 100 ml of methylene chloride solutioncontaining 19 ml (331 mmol) of acetyl chloride was dropped to thesolution. After stirring for 1 hour and 30 minutes, 5 ml of acetylchloride was further added to the mixture, and after 30 minutes, themixture was washed with 200 ml of water twice. After drying overmagnesium sulfate, the solvent was removed by distillation to obtain76.5 g of 2-(2-acetoxyethyl)-3,4-difluoronitrobenzene.

43 g of iron powder and 4 ml of concentrated hydrochloric acid wereadded to 450 ml of water and 100 ml of ethanol. The solution was heatedat 80° C., and, while well stirring, the obtained nitro compound wasdropped to the solution through 30 minutes. The solution was stirred for1 hour. After the solution was air-cooled, 500 ml of ethyl acetate wasadded to the filtrate, and the insoluble material was filtered. Theorganic layer was separated from the filtrate. After drying overmagnesium sulfate, the solvent was removed to obtain 61.2 g of2-(2-acetoxyethyl)-3,4-difluoroaniline. To this compound, 60 g (276mmol) of diethyl ethoxymethylenemalonate was added, and the mixture washeated at 120° C. for 5 hours. After air-cooled, the crystal wasfiltered off and washed with ether to obtain 78.2 g of the subjectcompound (2) in a 74% yield.

REFERENCE EXAMPLE 3:

Ethyl 6,7-Difluoro-4-hydroxy-8-(2-hydroxyethyl)quinoline-3-carboxylate(3):

78 g (203 mmol) of the compound (2) obtained in Reference Example 2 wasadded to 1.0 l of Dowtherm A (Trade Name), and the mixture was boiledfor 2 minutes. After air-cooled, the precipitated crystal was filteredoff and washed with ether to obtain 32 g of a mixture of ethyl8-(2-acetoxyethyl)-6,7-difluoro-4-hydroxyquinoline-3-carboxylate andethyl 8,9-difluoro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate.The obtained mixture and 4.26 g of sodium ethoxide were added to 730 mlof ethanol, and the solution was heated under reflux for one day. Afterair-cooled to room temperature, 5.1 g of a precipitated pyrroloquinolinederivative crystal was filtered off, and the filtrate was concentratedto 150 ml. The crystal was filtered off and washed consecutively withethanol and ether to obtain 23.8 g of the subject compound (3) in a 40%yield.

REFERENCE EXAMPLE 4

Ethyl1-Amino-6,7-difluoro-8-(2-hydroxyethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(4):

6.13 g (20 mmol) of the quinoline compound (3) obtained in ReferenceExample 3 and 8.8 g (60 mmol) of anhydrous potassium carbonate wereadded to 100 ml of N,N-dimethylformamide, and the mixed solution wasstirred at room temperature for 4 hours. 20 g (NET 17 g, 82 mmol) ofmesitylenesulfonylhydroxyamine hydrate was dissolved in 100 ml ofmethylene chloride, and after drying over sodium sulfate, while coolingon ice, this methylene chloride solution was dropped to the mixedsolution through 20 minutes. The obtained solution was stirredovernight. Methylene chloride was removed under reduced pressure bydistillation, and 100 ml of water was added to the solution. Thesolution was stirred for 30 minutes at room temperature. The crystal wasfiltered off and washed successively with water, ethanol and ether toobtain 3.30 g of the subject compound (4) in a 53% yield.

EXAMPLE 1

Ethyl4,5-Difluoro-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(5):

11.3 g (36 mmol) of 1-aminoquinolone (4) obtained in Reference Example 4and 15.1 g (58 mmol) of triphenylphosphine were added to 300 ml oftetrahydrofuran, and to this mixed solution, 500 ml of tetrahydrofuransolution containing 9.9 g (57 mmol) of diethyl azodicarboxylate wasdropped through 3 hours at room temperature. The solution was stirredfor 3 hours as it was, and the solvent was removed by distillation. Thecrystal was dispersed in ethanol, and was filtered off and washedsuccessively with ethanol and ether to obtain 9.5 g of the subjectcompound (5) in a 89% yield. The result of the analysis of this compoundwas as follows.

¹ H-NMR (DMSO-d₆): 1.27 (t, J=7.3 Hz, 3H), 2.95 (t, J=5.1 Hz, 2H), 3.31(s, 3H), 3.40 (t, J=5.8 Hz, 2H), 4.21 (q, J=7.3 Hz, 2H), 6.86 (t, J=6.6Hz, 1H), 7.91 (dd, J=11.0 Hz, J=8.8 Hz, 1H), 8.42 (s, 1H)

EXAMPLE 2

(1) Methyl4,5-Difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(6):

To 9.5 g (33 mmol) of pyridocinnoline (5) obtained in Example 1, 95 mlof dimethylsulfate was added, and the mixture was heated at 100° to 120°C. for 8 hours. After air-cooled, the solution was added to 900 ml ofwater containing 137 g of anhydrous potassium carbonate, and thesolution was stirred at room temperature for 30 minutes. The solutionwas extracted with 800 ml of chloroform and after drying over magnesiumsulfate, the solvent was removed by distillation. The residue waspurified by silica gel chromatography (250 g of silica gel, eluentsolvent: chloroform), and the obtained crystal was filtered off andwashed with ether to obtain 5.3 g of the subject compound (6) in a 56%yield. The result of the analysis of this compound was as follows.

¹ H-NMR (CDCl₃): 2.87 (s, 3H), 3.09 (t, J=6.2 Hz, 2H), 3.50 (t, J=6.2Hz, 2H), 3.93 (s, 3H), 8.17 (dd, J=9.6 Hz, J=9.5 Hz, 1H), 8.61 (s, 1H)

(2) The following compound (7) was obtained in the similar manner asExample 2 (1).

Ethyl4,5-Difluoro-2,3-dihydro-1-ethyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(7):

The result of the analysis of this compound was as follows.

¹ H-NMR (CDCl₃): 1.19 (t, J=6.9 Hz, 3H), 1.41 (t, J=7.0 Hz, 3H),2.96-3.06 (m, 4H), 3.56 (t, J=6.9 Hz, 2H), 4.39 (q, J=7.0 Hz, 2H), 8.14(dd, J=9.5 Hz, 9.5Hz, 1H), 8.54 (s, 1H)

EXAMPLE 3

(1)4,5-Difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (8): 5.3 g (18 mmol) of methyl ester (6) obtained in Example 2 (1)was added to 250 ml of tetrahydrofuran, and, while the solution washeated under reflux, 100 ml of aqueous solution containing 0.76 g (19mmol) of sodium hydroxide was added to the solution. The obtainedsolution was heated under reflux for 1.5 hours. After air-cooled, whilecooling on ice, the solution was neutralized with 4.2 g (20 mmol) ofcitric hydrate and stirred for 1 hour. The solid was filtered off andwashed consecutively with water, ethanol and ether to obtain 3.78 g ofthe subject compound (8) in a 75% yield.

The result of the analysis of this compound was as follows.

Colorless powder:

Melting point: 264°-265° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.88 (s, 3H), 3.14 (t, J=5.9 Hz, 2H), 3.54 (t, J=5.9Hz, 2H), 8.18 (dd, J=11 Hz, J=8 Hz, 1H), 8.82 (s, 1H)

(2) 29.1 g of methyl ester (6) obtained in Example 2 (1) was added to 80ml of concentrated hydrochloric acid and 320 ml of acetic acid, and thesolution was heated under reflux for 3.5 hours. After air-cooled, 500 mlof water was added to the solution, and the solid was filtered off andwashed consecutively with water, ethanol and ether to obtain 23.2 g ofcrude solid. The obtained crude solid was recrystallized from ethanoland chloroform to obtain 21 g of subject compound (8) in a 80% yield.The result of the analysis of this compound was as follows.

Colorless prisms:

Melting point: 264°-265° C. (decomp.)

(3) The following compound (9) was obtained in the similar manner asExample 3 (2).

4,5-Difluoro-2,3-dihydro-1-ethyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (9):

The result of the analysis of this compound was as follows.

Colorless prisms:

Melting point: 231° 232.5° C.

¹ H-NMR (DMSO-d₆): 1.09 (t, J=7.3 Hz, 3H), 3.01-3.12 (m, 4H), 3.61 (t,J=5.9 Hz, 2H), 8.16 (dd, J=10.3 Hz, 10.3 Hz, 1H), 8.71 (s, 1H)

(4) The following compound (10) was obtained in the similar manner asExample 3 (2).

4,5-Difluoro-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (10):

The result of the analysis of this compound was as follows.

Colorless powder:

Melting point: 265° C. (decomp.)

¹ H-NMR (DMSO-d₆): 3.03, 3.47 (each brs, each 2H), 7.27 (brs, 1H), 8.12(dd, J=8.4 Hz, 8.4 Hz, 1H), 8.68 (s, 1H)

EXAMPLE 4 (METHOD A) (1)4-(3-Aminopyrrolidin-1-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (11):

50 mg (0.18 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1)and 80 mg (0.93 mmol) of 3-aminopyrrolidine were added to 1 ml ofN,N-dimethylformamide, and the solution was heated at 100° C. for 1hour. Then, the solvent was removed by distillation, and distillatedtogether with toluene. Ethanol was added to the residue to solidify, andthe solid was filtered off and washed successively with ethanol andether to obtain 50 mg of the subject compound (11) in a 81% yield. Theresult of the analysis of this compound was as follows.

Colorless powder:

Melting point: 217°-218° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.65-1.76 (m, 1H), 2.01-2.11 (m, 1H), 2.91 (s, 3H),2.95 (t, J=5.5 Hz, 2H), 3.27-3.76 (m, 7H), 7.81 (d, J=14.2 Hz, 1H), 8.66(s, 1H)

(2) to (22): Compounds (12) to (29) and compound (101) to (103) shown inTables 3 to 7 were obtained according to the method A. The results ofthe analysis of these compounds were shown in Tables 3 to 7.

                                      TABLE 3                                     __________________________________________________________________________     ##STR21##                                                                    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    4(2)                                                                              12  CH.sub.3                                                                          ##STR22##   Colorless powder                                                                    219-220                                                                            DMF  DMSO-d.sub.6 1.05, 1.06(each s,                                               each 3H), 1.71-1.96(m, 2H),                                                   2.19-2.27 (m, 1H), 2.91(s, 3H),                                               3.34-3.73 (m, 8H), 7.83(d,                                                    J=14.3Hz, 1H), 8.67(s,                                                                         method A             4(3)                                                                              13  CH.sub.3                                                                          ##STR23##   Slightly yellowish powder                                                           245 decomp.                                                                        DMF  DMSO-d.sub.6  2.26(s, 3H),                                                    2.90(s, 3H), 3.05(t, J=5.5Hz,                                                 2H), 3.26, 3.34(each brs, each                                                4H), 3.46(t, J= 5.5Hz, 2H),                                                   7.91(d, J=12.5Hz, 1H), 8.74(s,                                                1H)              method A             4(4)                                                                              14  CH.sub.3                                                                          ##STR24##   Slightly pinkish powder                                                             207-209 decomp.                                                                    DMF  DMSO-d.sub.6 1.65-1.73(m, 1H),                                                2.02-2.10 (m, 1H), 2.91(s, 3H),                                               2.95(brs, 2H), 3.23-3.80(m, 7H),                                              7.81(d, J= 13.9Hz, 1H), 8.66(s,                                               1H)              method A             4(5)                                                                              15  CH.sub.3                                                                          ##STR25##   Slightly pinkish powder                                                             211-214 decomp.                                                                    DMF  DMSO-d.sub.6 1.65-1.72(m, 1H),                                                2.02- 2.09(m, 1H), 2.91(s, 3H),                                               2.95(brs, 2H), 3.34-3.78(m, 7H),                                              7.81(d, J= 13.9Hz, 1H), 8.66(s,                                               1H)              method A             4(6)                                                                              16  CH.sub.3                                                                          ##STR26##   Slightly yellowish powder                                                           236-239 decomp.                                                                    DMF  DMSO-d.sub.6 2.85(brs, 4H), 2.89                                              (s, 3H), 3.06(brs, 2H), 3.16                                                  (brs, 4H), 3.46(brs, 2H),                                                     7.91(d, J=12.1Hz, 1H), 8.73(s,                                                1H)              method               __________________________________________________________________________                                                             A                

                                      TABLE 4                                     __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    4(7)                                                                              17  CH.sub.3                                                                          ##STR27##   Slightly yellowish powder                                                           216-218 decomp.                                                                    DMF  DMSO-d.sub.6 1.01(d, J=5.5Hz,                                                 6H), 2.76-3.66,(m, 10H), 2.90(s,                                              3H), 7.91(d, J=13.5Hz, 1H),                                                   8.74(s, 1H)      method A             4(8)                                                                              18  CH.sub.3                                                                          ##STR28##   Slightly brown powder                                                               211-214 decomp.                                                                    DMF  DMSO-d.sub.6 1.17(d, J=5.1Hz,                                                 3H), 2.90(s, 3H), 3.08-3.71(m,                                                11H), 7.93 (d, J=13.2Hz, 1H),                                                 8.75(s, 1H)      method A             4(9)                                                                              19  CH.sub.3                                                                          ##STR29##   Slightly  yellowish powder                                                          275 decomp.                                                                        DMF  DMSO-d.sub.6 2.78(brs, 4H),                                                   2.90(s, 3H), 3.07(brs, 2H),                                                   3.45(brs, 6H), 7.93(d, J=11.7Hz,                                              1H), 8.75(s, 3H) method A             4(10)                                                                             20  CH.sub.3                                                                          ##STR30##   Slightly yellowish powder                                                           246-248                                                                            DMF  DMSO-d.sub.6 1.94(brs, 4H),                                                   2.91(s, 3H), 2.95(t, J=5, 1Hz,                                                2H), 3.42(t, J=5.9Hz, 2H),                                                    3.56(brs, 4H), 7.82(d, J=13.9Hz,                                              1H), 8.67(s, 1H) method A             4(11)                                                                             21  CH.sub.3                                                                          ##STR31##   Colorless powder                                                                    274 decomp.                                                                        DMF  DMSO-d.sub.6 2.90(s, 3H), 3.10(t,                                             J= 5.5Hz, 2H), 3.34(brs, 4H),                                                 3.69(t, J=4.8Hz, 2H), 3.76(brs,                                               4H), 7.93(d, J= 12.5Hz, 1H),                                                  8.75(s, 1H)      method A             4(12)                                                                             22  CH.sub.3                                                                          ##STR32##   Slightly brown powder                                                               252 decomp.                                                                        DMF  DMSO-d.sub.6 2.94(s, 3H), 3.10(t,                                             J= 5.5Hz, 2H), 3.48(t, J=5.5Hz,                                               2H), 4.83(s, 4H), 7.30-7.40(m,                                                4H), 7.95 (d, J=13.6Hz, 1H),                                                  8.75(s, 1H)      method               __________________________________________________________________________                                                             A                

                                      TABLE 5                                     __________________________________________________________________________    Ex- Com-                Melting                                               ample                                                                             pound               point                                                                              Reaction                    Preparing            No. No. R.sup.4                                                                          Y      Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR           method               __________________________________________________________________________    4(13)                                                                             23  CH.sub.3                                                                          ##STR33##                                                                           Slightly brown powder                                                               169 decomp.                                                                        DMF  DMSO-d.sub.6 2.91, 2.98, 2.99(each s,                                         each 3H), 3.02(t, J=5.9Hz, 2H), 3.45(t,                                       J= 5.9Hz, 2H), 7.89(d, J=13.2Hz, 1H),                                         8.72(s, 1H)            method A             4(14)                                                                             24  CH.sub.3                                                                          ##STR34##                                                                           Slightly brown powder                                                               256-261 decomp.                                                                    DMF  DMSO-d.sub.6 2.91(s, 3H), 3.01(t,                                             J=5.9Hz, 2H), 3.46(t, J=5.9Hz, 2H),                                           4.33(s, 4H), 6.05(s, 2H), 7.91(d,                                             J=13.6Hz, 1H), 8.72(s,                                                                               method A             4(15)                                                                             25  CH.sub.3                                                                          ##STR35##                                                                           Colorless powder                                                                    >300 DMF  DMSO-d.sub.6  2.89(brs, 2H), 2.95(s,                                          3H), 3.46(t, J=5.5Hz, 2H), 7.24, 7.62,                                        8.08(each s, each 1H), 8.21(d, J=9.5Hz,                                       1H), 8.87(s, 1H)       method               __________________________________________________________________________                                                             A                

                                      TABLE 6                                     __________________________________________________________________________    Ex- Com-                     Melting                                          ample                                                                             pound                    point                                                                              Reaction               Preparing            No. No. R.sup.4                                                                          Y           Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR      method               __________________________________________________________________________    4(16)                                                                             26  CH.sub.3                                                                          ##STR36##  Colorless prisms                                                                    228.5- 229.5                                                                       DMF  DMSO-d.sub.6 0.67(brs, 2H),                                                   0.71-0.75, 2.78-2.81(each m, each                                             2H), 2.81 (s, 3H), 3.02(brs, 1H),                                             3.46(t, J=5.9Hz, 2H), 6.40(brs,                                               1H), 7.79(d, J= 13.6Hz, 1H),                                                  8.59(s, 1H)       method A             4(17)                                                                             27  CH.sub.3                                                                          ##STR37##  Slightly brown powder                                                               213-215 decomp.                                                                    DMF  DMSO-d.sub.6 1.88(brs, 2H),                                                   2.90(s, 3H), 2.95, 3.03, 3.10,                                                3.35(each brs, each 2H), 3.49(brs,                                            4H), 7.92(d, J=13.5 Hz, 1H),                                                  8.74(s, 1H)       method A             4(18)                                                                             28  C.sub.2 H.sub.5                                                                   ##STR38##  Colorless powder                                                                    245-247 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.11(t, J=7.0Hz, 3H),                                            1.82- 1.96, 2.14-2.23(each m, each                                            1H), 2.97(brs, 2H), 3.09(q,                                                   J=7.0Hz, 2H), 3.43(t. J=6.6Hz,                                                2H), 3.65-3.85(m, 5H), 7.83(d,                                                J=13.9Hz, 1H), 8.58 (s,                                                                         method A             4(19)                                                                             29  C.sub.2 H.sub.5                                                                   ##STR39##  Slightly yellowish powder                                                           208  DMF  DMSO-d.sub.6 1.11(t, J=7.3Hz, 3H),                                            2.50 (s, 3H), 2.75-3.14(m, 8H),                                               3.54(brs, 2H), 7.93(d, J=12.8Hz,                                              1H), 8.65 (s, 1H) method               __________________________________________________________________________                                                             A                

                                      TABLE 7                                     __________________________________________________________________________    Ex- Com-                       Melting                                        ample                                                                             pound                      point                                                                              Reaction             Preparing            No. No. R.sup.4                                                                          Y             Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR    method               __________________________________________________________________________    4(20)                                                                             101 CH.sub.3                                                                          ##STR40##    Yellowish powder                                                                    171-175 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 2.91(s, 6H),                                                     3.00-3.16 (m, 1H), 3.18-3.75(m,                                               10H), 3.94 (brs, 1H), 7.83(d,                                                 J=16.2Hz, 1H), 8.68(s,                                                                        method A             4(21)                                                                             102 H                                                                                 ##STR41##    Yellowish powder                                                                    244-248                                                                            DMF  DMSO-d.sub.6 1.93(brs, 4H), 2.86                                              brs, 2H), 3.30(brs, 2H), 3.47(s,                                              H), 7.18(brs, 1H), 7.77(d,                                                    J=14.0 Hz, 1H), 8.55(s,                                                                       method A             4(22)                                                                             103 CH.sub.3                                                                          ##STR42##    Yellowish powder                                                                    145-148                                                                            DMF  DMSO-d.sub.6 1.02(d, J=6.3Hz,                                                 3H), 2.22(brs, 4H), 2.65(brs,                                                 2H), 2.91(s, 6H), 2.92-3.95(m,                                                5H), 7.95(d, J=12.8Hz, 1H),                                                   8.77(s, 1H)     method               __________________________________________________________________________                                                             A                

EXAMPLE 5 (METHOD B)

(1) 4-(cis (-)3-Amino-4-methylpyrrolidin-1-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (30):

1.0 g (3.6 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1),0.93 g (5.4 mmol) of cis (-) 3-amino-4-methylpyrrolidine dihydrochlorideand 2.95 g (19.4 mmol) of 1,8-diazabicyclo[5.4.01-7-undecene were addedto 20 ml of N,N-dimethylformamide, and the solution was heated at 110 to120° C. for 40 minutes. Then, the solvent was removed by distillation,and the solution was distillated together with toluene. 20 ml of ethanoland 1.2 g of acetic acid were added to the residue. The solution wasleft at room temperature as it was, and the precipitated solid wasfiltered off and washed successively with ethanol and ether to 750 mg ofthe subject compound (30) in a 58% yield. The result of the analysis ofthis compound was as follows.

Yellowish powder:

Melting point: 160°-162° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.07 (d, J=6.6 Hz, 3H), 2.39-2.44 (m, 1H), 2.91 (s,3H), 2.95 (brs, 2H), 3.21-3.70 (m, 6H), 3.94-3.99 (m, 1H), 7.82 (d,J=14.3 Hz, 1H), 8.67 (s, 1H)

The obtained powder was recystallized from a mixture solvent of ethanoland water and the crystal was analyzed by X-ray.

In the recrystallized crystal, a torsion angle between 3-amino group and4-methyl group on pyrrolidine ring was 48.9, and thus it was confirmedthat this was a cis conformation.

(2) to (26): Compounds (31) to (54) and compound (104) shown in Tables 8to 12 were obtained according to the B method. The results of theanalysis of these compounds were shown in Table 8 to 12.

                                      TABLE 8                                     __________________________________________________________________________     ##STR43##                                                                    Ex- Com-                    Melting                                           ample                                                                             pound                   point                                                                              Reaction                Preparing            No. No. R.sup.4                                                                          Y          Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR       method               __________________________________________________________________________    5(2)                                                                              31  CH.sub.3                                                                          ##STR44## Brown powder                                                                        179-182 decomp.                                                                    DMF  DMSO-d.sub.6 2.81(s, 3H), 2.97(brs,                                           2H), 4.11(brs, 1H), 7.82(d,                                                   J=13.5Hz, 1H), 8.60(s,                                                                           method B             5(3)                                                                              32  CH.sub.3                                                                          ##STR45## Colorless powder                                                                    239-242                                                                            DMF  DMSO-d.sub.6 1.82-1.91(m, 1H),                                                1.96- 2.06(m, 1H), 2.77-3.54(m,                                               6H), 2.91(s, 3H), 3.80-3.89(m, 2H),                                           4.40(brs, 1H), 5.04(d, J=3.7Hz,                                               1H), 7.82(d, J= 14.3 Hz, 1H),                                                 8.66(s, 1H)        method               __________________________________________________________________________                                                             B                

                                      TABLE 9                                     __________________________________________________________________________    Ex- Com-                    Melting                                           ample                                                                             pound                   point                                                                              Reaction                Preparing            No. No. R.sup.4                                                                          Y          Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR       method               __________________________________________________________________________    5(4)                                                                              33  CH.sub.3                                                                          ##STR46## Slightly yellowish powder                                                           235.5-237 decomp.                                                                  CH.sub.3 CN                                                                        DMSO-d.sub.6 1.82-1.91(m, 1H),                                                1.99-2.08(m, 1H), 2.75-3.14 (m,                                               2H), 2.91(s, 3H), 3.27-3.53(m, 4H),                                           .81-3.91(m, 2H), 4.41, 5.04(each                                              brs, each 1H), 7.82(d, J=14.2Hz,                                              1H), 8.66(s, 1H)   method B             5(5)                                                                              34  CH.sub.3                                                                          ##STR47## Colorless powder                                                                    235-238 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.82-1.91(m, 1H),                                                1.99-2.08(m, 1H), 2.75-3.14 (m,                                               2H), 2.91(s, 3H), 3.27-3.53(m, 4H),                                           .81-3.91(m, 2H), 4.41, 5.04(each                                              brs, each 1H), 7.82(d, J=14.2Hz,                                              1H), 8.66(s, 1H)   method B             5(6)                                                                              35  CH.sub.3                                                                          ##STR48## Slightly yellowish powder                                                           215 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.41(s, 3H),                                                     1.95-2.05(m, 2H), 2.91(s, 3H),                                                3.01(brs, 2H), 3.20- 3.63(m, 5H),                                             3.75-3.85 (m, 1H), 7.86(d,                                                    J=13.9Hz, 1H), 8.69(s,                                                                           method B             5(7)                                                                              36  CH.sub.3                                                                          ##STR49## Colorless powder                                                                    256-259 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 2.92, 3.37(each s,                                               each 3H), 3.08, 3.77(each brs, each                                           2H), 3.92-4.13(m, 4H), 7.89(d,                                                J=8.1Hz, 1H), 8.71(s,                                                                            method B             5(8)                                                                              37  CH.sub.3                                                                          ##STR50## Colorless powder                                                                    193-195                                                                            CH.sub.3 CN                                                                        DMSO-d.sub.6 1.08(d, J=6.2Hz, 3H),                                            1.79-1.86, 1.96-2.07(each m, each                                             1H), 2.90(s, 3H), 3.05-3.70 (m,                                               10H), 7.80(d, J=13.9Hz, 1H),                                                  8.65(s, 1H)        method B             5(9)                                                                              38  CH.sub.3                                                                          ##STR51## Colorless powder                                                                    235 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.00(d, J=8.1Hz, 3H),                                            2.22-2.31(m, 1H), 2.92(s, 3H),                                                3.60(d, J=5.4Hz, 2H), 3.80-3.90(m,                                            1H), 7.82(d, J=16.2Hz, 1H), 8.64(s,                                           1H)                method               __________________________________________________________________________                                                             B                

                                      TABLE 10                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    5(10)                                                                             39  CH.sub.3                                                                          ##STR52##   Slightly yellowish powder                                                           204-206 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.08(d, J=6.2Hz,                                                 3H), 1.90(s, 3H), 1.92-2.02(m,                                                1H), 2.91(s, 3H), 2.99-3.13(m,                                                2H), 3.33- 3.55(m, 5H),                                                       3.65-3.80(m, 2H), 7.81 (d,                                                    J=14.6Hz, 1H), 8.66(s,                                                                         method B             5(11)                                                                             40  CH.sub.3                                                                          ##STR53##   Slightly yellowish powder                                                           204-206 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.08(d, J=6.2Hz,                                                 3H), 1.90(s, 3H), 1.92-2.02(m,                                                1H), 2.91(s, 3H), 2.99-3.13(m,                                                2H), 3.33- 3.55(m, 5H),                                                       3.65-3.80(m, 2H), 7.81 (d,                                                    J=14.6Hz, 1H), 8.66(s,                                                                         method B             5(12)                                                                             41  CH.sub.3                                                                          ##STR54##   Colorless powder                                                                    246-247                                                                            CH.sub.3 CN                                                                        DMSO-d.sub.6 1.01(d, J=7.0Hz,                                                 3H), 2.35-2.45(m, 1H), 2.50, 2.91                                             each s, each 3H), 3.16(q,                                                     J=5.1Hz, 1H), 3.30(brs, 1H),                                                  3.35-3.54(m, 4H), 3.65-3.79(m,                                                2H), 7.80(d, J=14.3 Hz, 1H),                                                  8.64(s, 1H)      method B             5(13)                                                                             42  CH.sub.3                                                                          ##STR55##   Colorless powder                                                                    209-211                                                                            CH.sub.3 CN                                                                        DMSO-d.sub.6 1.19(d, J=6.2Hz,                                                 3H), 2.61, 2.92(each s, each 3H),                                             .00-3.23, 3.40-3.50(each m, each                                              3H), 3.65-3.74(m, 1H),                                                        3.81-3.95(m, 2H), 7.89(d,                                                     J=13.6Hz, 1H), 8.72(s,                                                                         method B             5(14)                                                                             43  CH.sub.3                                                                          ##STR56##   Slightly yellowish  powder                                                          223.5 decomp.                                                                      CH.sub.3 CN                                                                        DMSO-d.sub.6 1.38(s, 3H),                                                     1.89(brs, 2H), 2.78-2.88(m, 1H)                                               2.91(s, 3H), 3.01-3.18(m, 1H),                                                3.30-3.66(m, 5H), 3.94, 4.84(each                                             brs, each 1H), 7.80(d, J=14.3Hz,                                              1H), 8.65(s, 1H) method B             5(15)                                                                             44  CH.sub.3                                                                          ##STR57##   Slightly yellowish powder                                                           155 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.11(d, J=6.6Hz,                                                 3H), 2.05-2.16(m, 1H), 2.91(s,                                                3H), 3.05-3.57(m, 7H), 3.75(brs,                                              2H), 7.83(d, J=13.9Hz, 1H),                                                   8.67(s, 1H)      method               __________________________________________________________________________                                                             B                

                                      TABLE 11                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    5(16)                                                                             45  CH.sub.3                                                                          ##STR58##   Slightly yellowish powder                                                           157 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.11(d, J=6.6Hz,                                                 3H), 2.05-2.16(m, 1H), 2.91 (s,                                               3H), 3.05-3.57(m, 7H), 3.75 (brs,                                             2H), 7.83(d, J=13.9Hz, 1H),                                                   8.67(s, 1H)      method B             5(17)                                                                             46  CH.sub.3                                                                          ##STR59##   Slightly yellowish powder                                                           184-186 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.07(d, J=7.0Hz,                                                 3H), 2.91(s, 3H), 2.95-3.70(m,                                                8H), 3.94-4.03(m, 1H), 7.84(d,                                                J=14.6Hz, 1H), 8.67(s,                                                                         method B             5(18)                                                                             47  CH.sub.3                                                                          ##STR60##   Colorless powder                                                                    219-222 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 2.66-2.76(m, 1H),                                                2.91(s, 3H), 2.91-3.75(m, 12H),                                               3.89-3.98(m, 1H), 7.83(d, J=                                                  13.9Hz, 1H), 8.67(s,                                                                           method B             5(19)                                                                             48  CH.sub.3                                                                          ##STR61##   Slightly yellowish powder                                                           224-226 decomp.                                                                    CH.sub.3 CN                                                                        CDCl.sub.3 1.16(d, J=6.9Hz, 3H),                                              2.27-2.40(m, 1H), 2.93(s, 3H),                                                2.98(t, J=6.2Hz, 2H),                                                         3.16-3.25(m, 1H), 3.40-3.52(m,                                                4H), 3.85-3.95(m, 2H), 4.15(brs,                                              1H), 7.98 (d, J=13.6Hz, 1H),                                                  8.78(s, 1H)      method B             5(20)                                                                             49  CH.sub.3                                                                          ##STR62##   Slightly yellowish powder                                                           227-229 decomp.                                                                    CH.sub.3 CN                                                                        CDCl.sub.3 1.20(d, J=6.6Hz, 3H),                                              2.35-2.50(m, 1H), 2.82(t,                                                     J=8.0Hz, 2H), 2.93(s, 3H),                                                    3.08-3.23(m, 1H), 3.34-3.57(m,                                                4H), 3.61-3.70(m, 1H),                                                        4.01-4.12(m, 1H), 4.37(brs, 1H),                                              7.92(d, J=14.3Hz, 1H), 8.75(s,                                                1H)              method B             5(21)                                                                             50  CH.sub.3                                                                          ##STR63##   Slightly brown powder                                                               195 decomp.                                                                        DMF  DMSO-d.sub.6 2.82(s, 3H), 3.31(s,                                             4H), 6.21(brs, 1H), 7.79(d,                                                   J=13.5Hz, 1H), 8.59(s,                                                                         method               __________________________________________________________________________                                                             B                

                                      TABLE 12                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    5(22)                                                                             51  C.sub.2 H.sub.5                                                                   ##STR64##   Yellowish prisms                                                                    226-228 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.11(t, J=7.7Hz,                                                 3H), 1.81-1.91, 1.98-2.09(each m,                                             ach 1H), 3.09(q, J=7.3Hz, 3H),                                                3.30 (brs, 2H), 3.36-3.60,                                                    3.76-3.92 (each m, each 3H),                                                  4.40(brs, 1H), 5.00(brs, 1H),                                                 7.82(d, J=14.3Hz, 1H), 8.56(s,                                                1H)              method B             5(23)                                                                             52  C.sub.2 H.sub.5                                                                   ##STR65##   Slightly yellowish powder                                                           235-237.5 decomp.                                                                  CH.sub.3 CN                                                                        DMSO-d.sub.6 1.02(d, J=5.4Hz,                                                 3H), 1.12(t, J=5.4Hz, 3H), 2.85                                               (brs, 2H), 2.95- 3.70(m, 9H),                                                 3.75- 3.87(m, 1H), 7.83(d,                                                    J=16.3Hz, 1H), 8.57(s,                                                                         method B             5(24)                                                                             53  H                                                                                 ##STR66##   Slightly brown powder                                                               247-250 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.10(d, J=6.6Hz,                                                 3H), 2.95, 3.31(each brs, each                                                2H), 3.44-3.55(m, 3H), 3.76,                                                  3.94, 7.21(each brs, each 1H),                                                7.83 (d, J=13.9Hz, 1H), 8.58(s,                                               1H)              method B             5(25)                                                                             54  H                                                                                 ##STR67##   Slightly brown powder                                                               180 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.01(d, J=5.4Hz,                                                 3H), 1.56-1.70(m, 1H), 2.65-2.95                                              (m, 4H), 3.17-3.60(m, 5H), 3.72-                                              3.79(m, 1H), 7.25(brs, 1H),                                                   7.82(d, J= 13.5Hz, 1H), 8.57(s,                                               1H)              method B             5(26)                                                                             104 CH.sub.3                                                                          ##STR68##   Colorless prisms                                                                    182-183 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.06(d, J=6.2Hz,                                                 3H), 1.57-1.70(m, 1H), 1.95-2.10,                                             .75-2.83(each m, each 2H), 2.91                                               (s, 3H), 3.10-3.55(m, 6H),                                                    3.70-3.80(m, 1H), 7.82(d,                                                     J=13.9Hz, 1H), 8.66(s,                                                                         method               __________________________________________________________________________                                                             B                

EXAMPLE 6 (METHOD C)

(1)4-(3,7-Diazabicyclo[3.3.0]octan-3-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid Hydrochloride (55):

50 mg (0.18 mmol) of 4,5-difluoro compound (8) obtained in Example 3(1), 92 mg (0.34 mmol) of3-t-butoxycarbonyl-3,7-diazabicyclo[3.3.0]octane carbonate and 109 mg(0.72 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 1 ml ofN,N-dimethylformamide, and the solution was heated at 110° to 120° C.for 40 minutes. Then, the solvent was removed by distillation, and 20 mlof chloroform and 10 ml of water were added to the residue. The solutionwas acidified with citric acid. The organic layer was separated from thesolution and was removed by distillation after drying over sodiumsulfate. The solution was distillated together with toluene, and ethanolwas added to the residue to disperse the solid. The solid was filteredoff and washed consecutively with ethanol and ether to obtain 40 mg ofthe solid. Then, to the obtained solid, 0.9 ml of acetic acid and 0.2 mlof concentrated hydrochloric acid were added. The solution was stirredat room temperature for 15 minutes, and the solvent was removed bydistillation. The residue was distillated together with ethanol, and theresidue was tritulated with ethanol. The solid was filtered off andwashed successively with ethanol and ether to obtain 25 mg of thesubject compound (55) in a 34% yield. The results of the analysis ofthis compound were as follows:

Yellowish powder:

Melting point: 265°-269° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.91 (s, 3H), 2.93-3.19 (m, 6H), 3.29-3.59 (m, 8H),7.92 (d, J=13.2 Hz, 1H), 8.74 (s, 1H), 9.06 (brs, 2H)

(2) to (18): Compounds (56) to (71) and compound (105) shown in Tables13 to 16 were obtained according to the method C. The results of theanalysis of these compounds were shown in Table 13 to 16.

                                      TABLE 13                                    __________________________________________________________________________     ##STR69##                                                                    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    6(2)                                                                              56  CH.sub.3                                                                          ##STR70##   Yellowish powder                                                                    196 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.17(d, J=6.8Hz,                                                 3H), 2.40-2.44(m, 1H), 2.91(s,                                                3H), 2.98(brs, 2H), 3.22-3.64 (m,                                             6H), 3.78-3.90(m, 1H), 7.89(d,                                                J=13.7Hz, 1H), 8.39 (brs, 2H),                                                8.71(s, 1H)      method C             6(3)                                                                              57  CH.sub.3                                                                          ##STR71##    Yellowish powder                                                                   245 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 0.97(t, J=6.9Hz,                                                 3H), 1.46, 1.61(each quint, each                                              J=8.1Hz, each 1H), 2.40-2.47(m,                                               1H), 2.92(s, 3H), 3.09(brs, 2H),                                              3.30-3.42 (m, 1H), 3.50-3.73(m,                                               4H), 3.85-3.95, 4.07-4.18 (each                                               m, each 1H), 7.86(d, J=14.3Hz,                                                1H), 8.37(brs, 2H), 8.69(s,                                                                    method C             6(4)                                                                              58  CH.sub.3                                                                          ##STR72##   Slightly yellowish powder                                                           240-242                                                                            CH.sub.3 CN                                                                        DMSO-d.sub.6 0.95(t, J=7.3Hz,                                                 3H), 1.44, 1.73(each quint, each                                              J=7.0 Hz, each 1H), 2.20-2.30(m,                                              1H), 2.92(s, 3H), 3.01-3.14(m,                                                2H), 3.25 (t, J=8.1Hz, 1H),                                                   3.45(t, J=5.9Hz, 2H),                                                         3.55-3.63(m, 2H), 3.86(t, J=                                                  8.4Hz, 2H), 7.88(d, J=1 3.6Hz,                                                1H), 8.47(brs, 2H), 8.71(s,                                                                    method C             6(5)                                                                              59  CH.sub.3                                                                          ##STR73##   Yellowish powder                                                                    192-194                                                                            CH.sub.3 CN                                                                        DMSO-d.sub.6 1.13(d, J= 6.6Hz,                                                3H), 2.62-2.67(m, 1H), 2.91(s,                                                3H), 3.04(brs, 2H), 3.30-3.70(m,                                              5H), 3.85(brs, 1H)4.05-4.08(m,                                                1H), 7.87(d, J=13.9Hz, 1H),                                                   8.29(brs, 2H), 8.70(s,                                                                         method               __________________________________________________________________________                                                             C                

                                      TABLE 14                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    6(6)                                                                              60  CH.sub.3                                                                          ##STR74##   Yellowish powder                                                                    175 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 2.12-2.25, 2.27-2.43                                             each m, each 1H), 2.62(s, 3H),                                                2.94(s, 3H), 3.13-3.20(m, 1H),                                                3.37- 3.60(m, 4H), 3.75,                                                      3.83(each brs, each 2H), 7.89(d,                                              J=13.5Hz, 1H), 8.72(s, 1H),                                                   9.44(brs, 2H)    method C             6(7)                                                                              61  CH.sub.3                                                                          ##STR75##   Yellowish powder                                                                    197 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.78(q, J=4.7Hz,                                                 1H), 2.15(q, J=6.4Hz, 1H),                                                    2.55-2.60 (m, 1H), 2.91(s, 3H),                                               2.95-3.00 (m, 4H), 3.32-3.52,                                                 3.57-3.70 (each m, each 3H), 7.85                                             d, J=13.7Hz, 1H), 8.13(brs, 2H),                                              8.67(s, 1H)      method C             6(8)                                                                              62  CH.sub.3                                                                          ##STR76##   Slightly yellowish powder                                                           231-233 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 2.82-2.97(m, 1H),                                                2.93 (s, 3H), 3.06-3.20(m, 1H),                                               3.40(s, 3H), 3.35-3.52(m, 2H),                                                3.65-3.88 (m, 4H), 3.91-4.02(m,                                               1H), 4.18(brs, 1H), 7.88(d,                                                   J=14.1Hz, 1H), 8.44 (brs, 1H),                                                8.71(s, 1H)      method C             6(9)                                                                              63  CH.sub.3                                                                          ##STR77##   Slightly brown powder                                                               165 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.27(t, J=7.3Hz,                                                 3H), 2.11-2.24, 2.28-2.39(each m,                                             ach 1H), 2.92(s, 3H), 3.02(brs,                                               2H), 3.45(t, J=5.6Hz, 2H), 3.52-                                              3.59(m, 1H), 3.69-3.91(m, 4H),                                                7.89 (d, J=13.7Hz, 1H), 8.72(s,                                               1H), 9.34 (brs,                                                                                method C              6(10)                                                                            64  CH.sub.3                                                                          ##STR78##   Yellowish powder                                                                    254-256 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.62-1.83, 2.14-2.26                                             each m, each 1H), 2.78, 2.82,                                                 2.91 (each s, each 3H),                                                       3.10-3.15(m, 1H), 3.22(t,                                                     J=5.4Hz, 2H), 3.36-3.76(m, 7H),                                               7.85(d, J=13.5Hz, 1H), 8.69 (s,                                               1H)              method               __________________________________________________________________________                                                             C                

                                      TABLE 15                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    6(11)                                                                             65  CH.sub.3                                                                          ##STR79##   Slightly yellowish powder                                                           268 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.74-1.85, 2.11-2.22                                             each m, each 1H), 2.57, 2.91(each                                             , each 3H), 2.61-2.70(m, 1H),                                                 3.03(brs, 2H), 3.40-3.53,                                                     3.57-3.72 (each m, each 3H),                                                  7.85(d, J=13.9 Hz, 1H), 8.69(s,                                               1H), 8.97(brs, 1H)                                                                             method C             6(12)                                                                             66  CH.sub.3                                                                          ##STR80##   Slightly yellowish powder                                                           182-184 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 1.25(t, J=6.6Hz,                                                 3H), 1.76-1.88, 2.11-2.22,                                                    2.40-2.50(each  m, each 1H),                                                  2.91(s, 3H), 3.04-3.18, 3.22-3.33(                                            each m, each 1H), 3.39- 3.60(m,                                               4H), 3.65-3.76(m, 1H), 7.85 (d,                                               J=13.9Hz, 1H), 8.17(brs, 2H),                                                 8.67(s, 1H)      meth od C            6(13)                                                                             67  CH.sub.3                                                                          ##STR81##   Slightly yellowish powder                                                           208 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.17, 1.21(each s,                                               each 3H), 2.91(s, 3H),                                                        2.95-3.14(m, 1H), 3.32-3.75(m,                                                7H), 4.03(t, J=13.5Hz, 1H),                                                   7.87(d, J=13.7Hz, 1H), 8.47 (brs,                                             2H), 8.69(s, 1H) method C             6(14)                                                                             68  CH.sub.3                                                                          ##STR82##   Colorless powder                                                                    245 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 2.21-2.31,                                                       2.35-2.44(each m, each 1H),                                                   2.82(brs, 6H), 2.92(s, 3H),                                                   2.94-3.00(m, 1H), 3.01-3.17(m,                                                1H), 3.45(brs, 2H), 3.54-3.65(m,                                              2H), 3.80(t, J=8.1Hz, 2H),                                                    3.97(brs, 1H), 7.91(d, J=13.5Hz,                                              1H), 8.72(s, 1H) method C             6(15)                                                                             69  CH.sub.3                                                                          ##STR83##   Yellowish powder                                                                    238-239.5 decomp.                                                                  CH.sub.3 CN                                                                        DMSO-d.sub.6 1.24(t, J=7.3Hz,                                                 3H), 1.75-1.86, 2.13-2.23,                                                    2.60-2.71(each m, each 1H),                                                   2.91(s, 3H), 2.93-3.10 (m, 5H),                                               3.40-3.55(m, 4H), 3.56- 3.72(m,                                               3H), 7.85(d, J=14.3Hz, 1H),                                                   8.68(s, 1H), 8.87(brs,                                                                         method               __________________________________________________________________________                                                             C                

                                      TABLE 16                                    __________________________________________________________________________    Ex- Com-                      Melting                                         ample                                                                             pound                     point                                                                              Reaction              Preparing            No. No. R.sup.4                                                                          Y            Property                                                                            (°C.)                                                                       solvent                                                                            .sup.1 H-NMR     method               __________________________________________________________________________    6(16)                                                                             70  CH.sub.3                                                                          ##STR84##   Yellowish powder                                                                    241 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.30(d, J=6.6Hz,                                                 3H), 1.68-1.81, 2.04-2.16,                                                    2.36-2.48, 2.75-2.88(each m, each                                             1H), 2.91(s, 3H), 3.13-3.79 (m,                                               8H), 7.84(d, J=13.9Hz, 1H),                                                   8.22(brs, 2H), 8.68(s,                                                                         method C             6(17)                                                                             71  C.sub.2 H.sub.5                                                                   ##STR85##   Yellowish powder                                                                    244 decomp.                                                                        CH.sub.3 CN                                                                        DMSO-d.sub.6 1.11(t, J=7.3Hz,                                                 3H), 1.14(d, J=6.9Hz, 3H),                                                    2.57-2.70 (m, 1H), 3.03-3.11(m,                                               4H), 3.40-  3.50(m, 1H),                                                      3.51-3.71(m, 4H), 3.84(brs, 1H)                                               4.03(t, J=8.1Hz, 2H), 7.85(d,                                                 J=14.3Hz, 1H), 8.40(brs, 2H),                                                 8.59(s, 1H)      method C             6(18)                                                                             105 CH.sub.3                                                                          ##STR86##   Slightly brown powder                                                               183-187 decomp.                                                                    CH.sub.3 CN                                                                        DMSO-d.sub.6 2.73(brs, 1H),                                                   2.92(s, 3H), 3.06(brs, 2H),                                                   3.26-3.96 (m, 7H), 4.10-4.32(m,                                               2H), 7.91 (d, J=16.2Hz, 1H),                                                  8.52(brs, 1H), 8.73(s,                                                                         method               __________________________________________________________________________                                                             C                

EXAMPLE 7 (METHOD D)

(1)5-Fluoro-4-{(pyrrolidin-3-yl)oxy]-2,3-dihydro-i-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid

Hydrochloride (72):

278 mg (1 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1)and 374 mg (2 mmol) of 1-t-butoxycarbonyl-3-pyrrolidinol were added to 3ml of N,N-dimethylformamide, and at room temperature 120 mg (3 mmol) ofsodium hydride was added to the solution. The solution was stirred as itwas, and the solvent was removed by distillation. Then, 15 ml ofchloroform and 10 ml of water were added to the solution, and thesolution was acidified with citric acid. The organic layer was separatedand was removed by distillation after drying over sodium sulfate. Thesolution was distillated together with toluene, and ether was added tothe residue to disperse the solid. The solid was filtered off to obtain314 mg of the solid. To 180 mg of the obtained solid, 4 ml of aceticacid and 1 ml of concentrated hydrochloric acid were added at roomtemperature. The solution was stirred at room temperature for 15 minutesas it was, and the solvent was removed by distillation. The residue wasdistillated together with ethanol, and the residue was tritulated withethanol. The solid was filtered off and washed successively with ethanoland ether to obtain 144 g of the subject compound (72) in a 67% yield.The result of the analysis of this compound was as follows.

Slightly yellowish powder:

Melting point: 241° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.12-2.31 (m, 2H), 2.89 (s, 3H), 2.98-3.59 (m, 8H),5.40 (brs, 1H), 8.06 (d, J=12.1 Hz, 1H), 8.78 (s, 1H), 9.60, 9.75 (eachbrs, each 1H)

(2) to (4): Compounds (73) to (75) shown in Table 17 were obtainedaccording to the method D. The results of the analysis of thesecompounds were shown in Table 17.

                                      TABLE 17                                    __________________________________________________________________________     ##STR87##                                                                    Ex- Com-                                                                      ample                                                                             pound                Melting                                                                             Reaction                  Preparing            No. No. R.sup.4                                                                          Y        Property                                                                           point (°C.)                                                                  solvent                                                                            .sup.1 H-NMR         method               __________________________________________________________________________    7(2)                                                                              73  CH.sub.3                                                                          ##STR88##                                                                             Colorless powder                                                                   204-206 decomp.                                                                          DMSO-d.sub.6 1.01(t, J=5.4Hz, 2H),                                            1.16(t, J=6.8Hz, 2H), 2.88(s, 3H),                                            3.18(t, J=5.4Hz, 2H), 3.52(t,                                                 J=5.9Hz, 2H), 4.41(s, 2H), 8.04(d,                                            J=12.2Hz, 1H), 8.78 (s, 1H),                                                  8.84(brs, 2H)        method D             7(3)                                                                              74  CH.sub.3                                                                          ##STR89##                                                                             Colorless powder                                                                   195-196.5 decomp.                                                                        DMSO-d.sub.6 2.87(s, 3H), 3.09, 3.51,                                         4.21, 4.37(each brs, each 2H,                                                 5.25(brs, 1H), 8.03(d, J=11.7Hz, 1H),                                         8.77(s, 1H)          method D             7(4)                                                                              75  C.sub.2 H.sub.5                                                                   ##STR90##                                                                             Colorless powder                                                                   229-231 decomp.                                                                          DMSO-d.sub.6 1.08(t, J=7.3Hz, 3H),                                            2.15-2.30(m, 2H), 2.90-3.17(m, 4H),                                           3.49(brs, 2H), 3.57(brs, 2H),                                                 5.39(brs, 1H), 8.03(d, J=12.1Hz, 1H),                                         8.67(s, 1H)          method               __________________________________________________________________________                                                             D                

EXAMPLE 8 (METHOD E)

5-Fluoro-4-methoxy-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (76):

50 mg (0.18 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1)and 30 mg of sodium methoxide were added to 5 ml of methanol, and thesolution was heated under reflux for 5.5 hours. After air-cooled, 0.5 mlof acetic acid and 10 ml of methanol were added to the solution. Thedeposited solid was filtered off and washed successively with methanoland ether to obtain 50 g of the subject compound (76) in a 96% yield.The result of the analysis of this compound was as follows.

Colorless powder:

Melting point: 236°-241° C.

¹ H-NMR (DMSO-d₆): 2.86 (s, 3H), 3.04 (t, J=5.9 Hz, 2H), 3.50 (t, J=6.2Hz, 2H), 4.10 (s, 3H), 8.02 (d, J=12.5 Hz, 1H), 8.76 (s, 1H),

EXAMPLE 9

(1) 4-(cis (-)3-Amino-4-methylpyrrolidin-1-yl)-S-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid Hydrochloride (77):

5.1 g of the compound (30) obtained in Example 5 (1) was dissolved in110 ml of acetic acid, and then 25 ml of concentrated hydrochloric acidwas added to the solution. The solution was stirred overnight at roomtemperature. The crystal was filtered off and washed successively withethanol and ether to obtain 4.6 g of crude crystal. The filtrate wasremoved by distillation, and 80 ml of ethanol was added to the residue,and the deposited crystal was filtered off. The combined crude crystalwas recrystallized from ethanol to obtain 4.61 g of the subject compound(77). The result of the analysis of this compound was as follows.

Yellowish prisms:

Melting point: 211°-214° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.15 (d, J=7.0 Hz, 3H), 2.57-2.70 (m, 1H), 2.91 (s,3H), 3.07 (brs, 2H), 3.30-3.72 (m, 5H), 3.84 (brs, 1H), 4.04-4.14 (m,1H), 7.84 (t, J=14.3 Hz, 1H), 8.68 (s, 1H),

(2) 4-(cis (-)3-Amino-4-methylpyrrolidin-1-yl)-5-fluoro-2,3-dihydro-i-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid Tosylate (78):

3.2 g of the compound (30) obtained in Example 5 (1) was dissolved in110 ml of chloroform and 110 ml of methanol, and then 40 ml of methanolsolution containing 6.37 g of p-toluenesufonic acid hydrate was added tothe solution. The solution was stirred at room temperature for 40minutes. The solvent was removed by distillation, and the crystal wasdispersed in ethanol. The crystal was filtered off and washedsuccessively with ethanol and ether to obtain 4.52 g of crude crystal.The crystal was recrystallized from a mixture solvent of ethanol andwater to obtain 4.52 g of the subject compound (78). The result of theanalysis of this compound was as follows.

Colorless needles:

Melting point: 258°-260° C.

¹ H-NMR (DMSO-d₆): 1.12 (d, J=6.9 Hz, 3H), 2.28, 2.91 (each s, each 3H),2.60-2.70 (m, 1H), 3.00 (brs, 2H), 3.35-3.68 (m, 5H), 3.88 (brs, 1H),4.01-4.06 (m, 1H), 7.10 (d, J=7.7 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.86(d, J=13.9 Hz, 1H), 8.69 (s, 1H),

(3) to (7): Compounds (79) to (83) shown in Table 18 were obtainedaccording to Example 9 (2). The results of the analysis of thesecompounds were shown in Table 18.

                                      TABLE 18                                    __________________________________________________________________________     ##STR91##                                                                    Ex.-                                                                              Com-                                                                      ample                                                                             pound                          Melting                                    No. No. Y          HX        Property                                                                            point (°C.)                                                                  .sup.1 H-NMR                         __________________________________________________________________________    9(3)                                                                              79                                                                                 ##STR92## HCl       Yellowish needles                                                                   >270 decomp.                                                                        DMSO-d.sub.6 1.29(d, J=6.2Hz,                                                 3H), 1.68-1.81, 2.04-2.18,                                                    2.36-2.48, 2.75-2.85 (each m,                                                 each 1H), 2.92(s, 3H),                                                        3.13-3.79(m, 8H), 7.85(d,                                                     J=14.3Hz, 1H), 8.69(s, 1H)           9(4)                                                                              80                                                                                 ##STR93## CH.sub.3 SO.sub.3 H                                                                     Slightly yellowish needles                                                           265 decomp.                                                                        DMSO-d.sub.6 1.12(d, J=7.0Hz,                                                 3H), 2.31, 2.92(each s, each                                                  3H), 2.60-2.70(m, 1H), 3.01(brs,                                              2H), 3.35-3.66(m, 5H), 3.88(brs,                                              1H), 4.00-4.08(m, 1H), 7.88(d,                                                J=13.9Hz, 1H), 8.70(s, 1H)           9(5)                                                                              81                                                                                 ##STR94## 1/2 H.sub.2 SO.sub.4                                                                    Yellowish prisms                                                                    202-205 decomp.                                                                     DMSO-d.sub.6 1.08(d, J=6.9Hz,                                                 3H), 2.91(s, 3H), 2.96(brs, 2H),                                              3.35-3.70(m, 6H), 3.92-4.03(m,                                                1H), 7.82(d, J=13.9Hz, 1H),                                                   8.66(s, 1H)                          9(6)                                                                              82                                                                                 ##STR95##                                                                                ##STR96##                                                                              Slightly yellowish prisms                                                           219-220 decomp.                                                                     DMSO-d.sub.6 1.07(d, J=6.6Hz,                                                 3H), 2.36-2.47(m, 1H), 2.91(s,                                                3H), 2.94-3.10(m,                                                             2H), 3.30-3.65(m, 6H),                                                        3.91-4.00(m, 1H), 6.42(s, 1H),                                                7.81(d, J=14.6Hz, 1H) 8.65(s,                                                 1H)                                  9(7)                                                                              83                                                                                 ##STR97##                                                                                ##STR98##                                                                              Slightly yellowish needles                                                          201-202                                                                             DMSO-d.sub.6 1.12(d, J=7.0Hz,                                                 3H), 2.60-2.70(m, 1H), 2.91(s,                                                3H), 3.00(brs, 2H) 3.35-3.68(m,                                               5H), 3.88(brs, 1H), 3.99-4.10(m,                                              H), 6.02(s, 2H), 7.87(d,                                                      J=14.3Hz, 1H), 8.70(s,               __________________________________________________________________________                                             1H)                              

EXAMPLE 10

(1) 4-{cis (-)3-(t-Butoxycarbonylaminoacetylamino)-4-methylpyrrolidin-1-yl}-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (84):

350 mg (2 mmol) of N-t-butoxycarbonylglycine and 202 mg (2 mmol) ofN-methylmorpholine were added to 6 ml of methylene chloride. The mixturesolution was cooled on freezing mixture, and 0.26 ml (2 mmol) ofisobutyl chlorocarbonate was added to the solution. After 20 minutes,716 mg (2 mmol) of the compound (30) obtained in Example 5 (1) was addedto the solution, and the solution was stirred at room temperature for 30minutes. Then, 10 ml of water was added to the solution, and thesolution was acidified with by citric acid. The organic layer wasseparated from the solution and was removed distillation after dryingover sodium sulfate. Ethyl acetate--ether was added to the residue, thenthe product came out of the solution, and the solid was filtered off toobtain 776 mg of the subject compound (84) in a 75% yield. The resultsof the analysis of this compound were as follows:

Yellowish powder:

Melting point: 142°-145° C.

¹ H-NMR (CDCl₃): 1.12 (d, J=7.0 Hz, 3H), 1.45 (s, 9H), 2.54-2.65 (m,1H), 2.87 (brs, 2H), 2.95 (s, 3H), 3.42-3.55 (m, 5H), 3.83-3.89 (m, 2H),3.98-4.05 (m, 1H), 4.62, 5.46, 7.05 (each brs, each 1H), 7.70 (d, J=13.5Hz, 1H), 8.63 (s, 1H),

(2) to (4): Compounds (85) to (87) shown in Table 19 were obtainedaccording to Example 10 (1). The results of the analysis of thesecompounds were shown in Table 19.

                                      TABLE 19                                    __________________________________________________________________________     ##STR99##                                                                    Ex- Com-                                                                      ample                                                                             pound                    Melting                                          No. No. Y              Property                                                                            point (°C.)                                                                  .sup.1 H-NMR                               __________________________________________________________________________    10(2)                                                                             85                                                                                 ##STR100##    Slightly yellowish powder                                                           248-249.5                                                                           CDCl.sub.3 1.08, 1.38(each d, each                                            J=7.0Hz, each 3H), 1.46(s, 9H),                                               2.55-2.66(m, 1H), 2.93(s, 5H),                                                3.35-3.60(m, 5H), 3.95-4.05,                                                  4.10-4.20(each m, each 1H), 4.61(brs,                                         1H), 4.97(d, J=7.7Hz, 1H), 6.99(d,                                            J=5.4Hz, 1H), 7.89(d, J=13.9Hz, 1H),                                          8.72(s, 1H)                                10(3)                                                                             86                                                                                 ##STR101##    Colorless powder                                                                    147-148                                                                             CDCl.sub.3 0.96(d, J=6.9Hz, 3H),                                              0.99(d, J= 8.1Hz, 3H), 1.07(d,                                                J=6.6Hz, 3H), 2.15-2.30(m, 1H),                                               2.50-2.65(m, 1H), 2.80-3.10(m, 2H),                                           2.93(s, 3H), 3.35-3.60(m, 5H),                                                3.95-4.10(m, 2H), 4.60(brs, 1H),                                              5.12(s, 2H), 5.46(d, J=9.2Hz, 1H),                                            6.77(d, J=8.0Hz, 1H), 7.31-7.33(m,                                            5H), 7.75(d, J=13.6Hz, 1H), 8.64(s,                                           1H)                                        10(4)                                                                             87                                                                                 ##STR102##    Yellowish powder                                                                    140-141 decomp.                                                                     CDCl.sub.3 1.39(d, J=7.0Hz, 3H),                                              1.45(s, 9H), 2.02-2.15, 2.20-2.38(each                                        m, each 1H), 2.94(s, 3H), 3.05(brs,                                           2H), 3.48(brs, 4H),  3.86(brs, 2H),                                           4.20, 4.56, 5.23, 7.22(each brs, each                                         1H),  7.77(d, J=13.5Hz, 1H), 8.64(s,                                          1H)                                        __________________________________________________________________________

EXAMPLE 11

(1) 4-{cis (-)3-(Aminoacetylamino)-4-methylpyrrolidin-1-yl}-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylicacid Hydrochloride (88):

750 mg (1.5 mmol) of the compound (84) obtained in Example 10 (1) wasadded to 10 ml of dioxane and 10 ml of ethanol, and then 2.5 ml of 4Nhydrochloric acid solution in dioxane was added to the solution. Thesolution was stirred at room temperature for 1 hour, and the solvent wasremoved by distillation. The powder was filtered off and washedsuccessively with ethanol and ether to obtain 324 mg of the subjectcompound (88) in a 49% yield. The result of the analysis of thiscompound was as follows.

Yellowish powder:

Melting point: 196° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.01 (d, J=6.6 Hz, 3H), 2.91 (s, 3H), 3.00 (brs, 2H),3.30-3.70 (m, 7H), 4.06, 4.49 (each brs, each 1H), 7.83 (d, J=14.3 Hz,1H), 8.13, 8.67 (each brs, each 2H),

(2) to (8): Compounds (89) to (94) and compound (106) shown in Tables 20and 21 were obtained according to Example 11 (1). The results of theanalysis of these compounds were shown in Tables 20 and 21.

                                      TABLE 20                                    __________________________________________________________________________     ##STR103##                                                                   Ex- Com-                        Melting                                       ample                                                                             pound                       point                                         No. No. Y                 Property                                                                            (°C.)                                                                       .sup.1 H-NMR                             __________________________________________________________________________    11(2)                                                                             89                                                                                 ##STR104##       Yellowish powder                                                                    198-200                                                                            DMSO-d.sub.6 1.03, 1.36(each d, each                                          J=6.9Hz, each 3H), 2.91(s, 3H),                                               3.02(brs, 2H), 3.30-3.70(m, 5H),                                              3.90-4.10(m, 2H), 4.46(brs, 1H),                                              7.82 (d, J=14.3Hz, 1H), 8.26,                                                 8.66(each brs, each 2H)                  11(3)                                                                             90                                                                                 ##STR105##       Yellowish powder                                                                    186-189 decomp.                                                                    DMSO-d.sub.6 0.67(d, J=7.0Hz, 3H),                                            2.31-2.45(m, 1H), 2.91(s, 3H),                                                2.98(brs, 2H), 3.07(d, J=7.3Hz, 2H),                                          3.32-3.60(m, 5H), 3.96-4.06 (m, 1H),                                          4.21(t, J=6.6Hz, 1H), 4.37(brs, 1H),                                          7.32(brs, 5H), 7.81(d, J=14.6Hz,                                              1H), 8.35(brs, 2H), 8.66(s, 1H),                                              8.71(d, J=8.0Hz, 1H)                     11(4)                                                                             91                                                                                 ##STR106##       Yellowish powder                                                                    195 decomp.                                                                        DMSO-d.sub.6 0.97(d, J=6.6Hz, 3H),                                            1.53, 1.56, 2.91(each s, each 3H),                                            3.03(brs, 2H), 3.35-3.54 (m, 4H),                                             3.75, 3.96, 4.52(each brs, each 1H),                                          7.83 (d, J=14.3Hz, 1H), 8.34(brs,                                             3H), 8.67(s, 1H)                         11(5)                                                                             92                                                                                 ##STR107##       Yellowish powder                                                                    177-180                                                                            DMSO-d.sub.6 0.88(d, J=5.5Hz, 3H),                                            0.90(d, J=6.6Hz, 3H), 1.07(d,                                                 J=6.2Hz, 3H), 1.61(brs, 3H), 2.92(s,                                          3H), 3.05(brs, 2H), 3.35-3.75 (m,                                             5H), 4.02(brs, 2H), 4.47(brs, 1H),                                            7.81(d, J=13.9Hz, 1H), 8.41(brs,                                              2H), 8.66(s, 1H), 8.87(d, J=7.7Hz,                                            1H)                                      11(6)                                                                             93                                                                                 ##STR108##        Yellowish powder                                                                   194-197                                                                            DMSO-d.sub.6 0.97, 1.25, 1.35(each                                            brs, each 3H), 2.92(s, 3H),                                                   3.09(brs, 2H), 3.35-4.05(m, 8H),                                              4.45(brs, 1H), 7.85(d, J=13.5Hz,                                              1H), 8.20(brs, 3H), 8.67(brs,            __________________________________________________________________________                                         2H)                                  

                                      TABLE 21                                    __________________________________________________________________________     ##STR109##                                                                   Ex- Com-                     Melting                                          ample                                                                             pound                    point                                            No. No. Y              Property                                                                            (°C.)                                                                       .sup.1 H-NMR                                __________________________________________________________________________    11(7)                                                                              94                                                                                ##STR110##    Yellowish powder                                                                    260 decomp.                                                                        DMSO-d.sub.6 1.36(d,  J=7.0Hz, 3H),                                           1.91-2.01, 2.16-2.26(each m, each 1H),                                        2.92(s, 3H), 3.00(brs, 2H),                                                   3.37-3.64(m, 4H), 3.91-3.96(m, 3H),                                           4.41(brs, 1H), 7.83(d, J=13.9Hz, 1H),                                         8.27(brs, 2H), 8.68(s, 1H), 8.97(d,                                           J=6.6Hz, 1H)                                11(8)                                                                             106                                                                                ##STR111##    Yellowish powder                                                                    188-190                                                                            DMSO-d.sub.6 1.10-1.15(m, 3H), 1.36(d,                                        J=13.5Hz, 3H), 1.63-1.75, 2.00-2.10,                                          2.28-2.38, 2.78-2.85(each m, each 1H),                                        2.90(s, 3H), 3.00-3.10 (m, 1H),                                               3.37-3.58(m, 5H), 3.70-3.83(m, 3H),                                           7.85(d, J=13.5Hz, 1H), 8.20(brs, 2H),                                         8.51-8.61(m, 1H), 8.67(m,                   __________________________________________________________________________                                      1H)                                     

EXAMPLE 12

4-{cis (-)3-(2-Amino-3-methylbutanoyl)amino-4-methylpyrrolidin-1-yl}-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid Hydrochloride (95):

850 mg (1.4 mmol) of the compound (86) obtained in Example 10 (3) wasadded to 60 ml of methanol and 10 ml of acetic acid, and then 300 mg of5% palladium on carbon was added to the solution. The solution wasstirred overnight under hydrogen. Then, palladium on carbon wasfiltered, and the solvent was removed by distillation. The residue wasdissolved in 10 ml of methanol, and 2 ml of 4N hydrochloric acidsolution in dioxane was added to the solution. The solvent was removedby distillation. The powder was filtered off and washed successivelywith ethanol and ether to obtain 600 mg of the subject compound (95) ina 87% yield. The result of the analysis of this compound was as follows.

Yellowish powder:

Melting point: 198°-199.5° C. (decomp.)

¹ H-NMR (DMSO-d₆): 0.93 (d, J=6.6 Hz, 6H), 1.07 (d, J=6.6 Hz, 3H),2.05-2.15 (m, 1H), 2.91 (s, 3H), 3.02 (brs, 2H), 3.30-3.50 (m, 3H), 3.62(t, J=8.4 Hz, 2H), 3.80, 4.04, 4.48 (each brs, each 1H), 7.82 (d, J=14.3Hz, 1H), 8.29 (brs, 2H), 8.66 (s, 1H), 8,73 (d, J=7.7 Hz, 1H)

EXAMPLE 13

4-{cis (-)3-((2-Amino-3-methylbutanoyl)aminoacetylamino)-4-methylpyrrolidin-1-yl}-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid Hydrochloride (96):

758 mg (2 mmol) of (N-t-butoxycarbonylvalyl)glycine p-nitrophenyl ester,202 mg (2 mmol) of triethylamine and 716 mg (2 mmol) of the compound(30) obtained in Example 5 (1) were added to 10 ml of methylenechloride. The mixture solution was stirred overnight at roomtemperature. 10 ml of water was added to the solution and the solutionwas acidified with citric acid. The organic layer was separated and wasremoved by distillation after drying over sodium sulfate. Ethylacetate--ether was added to the residue, the product came out of thesolution, and the solid was filtered off. The solid was added to 10 miof methanol, and 2.5 ml of 4N hydrochloride solution in dioxane wasadded to the solution. After the solution was stirred at roomtemperature for 30 minutes, the solvent was removed by distillation. Thepowder was filtered off and washed successively with ethanol and etherto obtain 618 mg of the subject compound (96) in a 58% yield. Theresults of the analysis of this compound were as follows:

Yellowish powder:

Melting point: 189°-191° C.

¹ H-NMR (DMSO-d₆): 0.94-1.00 (m, 9H), 2.00-2.18 (m, 1H), 2.91 (s, 3H),3.01 (brs, 2H), 3.30-3.55 (m, 4H), 3.65 (brs, 2H), 3.73-3.89 (m, 1H),3.94-4.05 (m, 2H), 4.47 (brs, 1H), 7.82 (d, J=14.3 Hz, 1H), 8.22 (brs,3H), 8.66 (s, 1H), 8,74 (brs, 1H)

EXAMPLE 14

Ethyl1-Amino-6,7-difluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(97):

10.7 g (32.9 mmol) of ethyl6,7-difluoro-4-hydroxy-8-acetoxymethylquinoline-3-carboxylate and 14.2 g(65.8 mmol) of anhydrous potassium carbonate were added to 130 ml ofN,N-dimethylformamide, and the solution was stirred at room temperaturefor 4 hours. 14 g (NET 8.97 g, 49 mmol) ofmesitylenesulfonylhydroxyamine was dissolved in 100 ml of methylenechloride, and after drying over sodium sulfate, while cooling on ice,this solution was dropped to the previous solution through 20 minutes.Then, the obtained solution was left overnight as it was. To thissolution, 100 ml of water was added, and the solution was stirred atroom temperature for 1 hour. The solution was extracted with methylenechloride, and the organic layer was washed. After drying over sodiumsulfate, the solvent was removed under reduced pressure and ether wasadded to the crystal residue. The crystals were filtered off and washedwith ether to obtain 6.4 g of the subject compound (97) in a 57% yield.The results of the analysis of this compound were as follows:

Colorless needles:

Melting point: 217°-221° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.3 Hz, 3H), 2.05 (s, 3H), 4.25 (q, J=7.3Hz, 2H), 5.74 (s, 2H), 6.59 (brs, 2H), 8.15 (dd, J=9.2 Hz, 10.3 Hz, 1H),8.59 (s, 1H)

EXAMPLE 15

Ethyl1-Acetoamino-6,7-difluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(98):

2 g (5.8 mmol) of 1-aminoquinoline (97) obtained in Example 14 and 80 mgof sodium ethoxide were added to 60 ml of ethanol, and the solution washeated at reflux for 1 day. After air-cooled to room temperature, thedeposited crystal was filtered off, and filtrate was concentrated. Thecrystals were filtered off and washed consecutively with ethanol andether to obtain 1.8 g of the subject compound (98) in a 90% yield. Theresults of the analysis of this compound were as follows:

Colorless needles:

Melting point: 243°-248° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.0 Hz, 3H), 2.04 (s, 3H), 4.25 (q, J=7.1Hz, 2H), 4.82 (brs, 2H), 8.09 (dd, J=8.8 Hz, 10.3 Hz, 1H), 8.42 (s, 1H)

EXAMPLE 16

Ethyl3,4-Difluoro-1,2-dihydro-1-acetyl-6-oxo-1H,6H-pyrido[3,2,1-hi]indazole-7-carboxylate(99):

0.85 g (2.5 mmol) of the compound (98) obtained in Example 15 and 0.98 g(3.75 mmol) of triphenylphosphine were added to 20 ml oftetrahydrofuran, and at room temperature 30 ml of tetrahydrofuransolution containing 0.65 g (3.75 mmol) of diethyl azodicarboxylate wasdropped to the solution through 3 hours. The solution was left overnightas it was, and the solvent was removed by distillation. The crystalswere dispersed in ether, filtered off and washed consecutively withethanol and ether to obtain 0.51 g of the subject compound (99) in a 63%yield. The results of the analysis of this compound were as follows:

Colorless needles:

Melting point: 235°-237° C. (decomp.

¹ H-NMR (DMSO-d₆): 1.27 (t, J=6.6 Hz, 3H), 2.31 (s, 3H), 4.23 (q, J=7.3Hz, 2H), 5.67 (s, 2H), 7.84 (dd, J=7.3 Hz, 10.3 Hz, 1H), 9.49 (s, 1H)

EXAMPLE 17

3,4-Difluoro-1,2-dihydro-6-oxo-1H,6H-pyrido[3,2,1-hi]-indazole-7-carboxylicacid (100):

0.51 g (1.55 mmol) of the compound (99) obtained in Example 16 was addedto 5 ml of a mixture solution of concentrated hydrochloric acid andacetic acid (in a volumetic ratio of 1:4), and this solution was heatedat reflux for 8 hours. After air-cooled, the solution was diluted with100 ml of water, and the deposited crystals were filtered and washedconsecutively with water, ethanol and ether to obtain 200 mg of thesubject compound (100) in a 51% yield. The results of the analysis ofthis compound were as follows:

Colorless needles:

Melting point: 232°-237° C. (decomp.)

¹ H-NMR (DMSO-d₆): 4.99 (s, 2H), 8.02 (dd, J=7.0 Hz, 3.3 Hz, 1H), 8.96(s, 1H)

EXAMPLE 18

4,5-Difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid BF, chelate (107):

2.78 g of compound (8) obtained in Example 3 was suspended in 30 mi ofether, to which 80 ml of boron trifluoride-ether complex was added over5 minutes while cooling on ice. Stirring was continued overnight, andprecipitated solid was collected by filtration. 3.07 g of a titlecompound (107) was obtained (yield: 94%).

Colorless powder

Melting point: 285° C. (decomp.)

¹ H-NMR(DMSO-d₆): 3.01 (s, 1H), 3.25, 3.64 (each brs, each 2H), 8.49(dd, J=9.0Hz, 9.0Hz 1H), 9.38 (s, 1H)

EXAMPLE 19 (METHOD F)

(1)4-((3R)-Methylpiperazin-1-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid (108): 2 ml ofdimethylsulfoxide was added to 164 mg (0.5 mmol) of compound (107), 173mg (1 mmol) of (2R)-methylpiperazine.2HCl and 0.36 ml (2.5 mmol) oftriethylamine, and stirred overnight at room temperature. Ether wasadded thereto, supernatant was removed, and ethanol and ether were addedto the residue for collecting crystals. The crystals were washed withether, and added with 20 ml of aqueous 80% methanol solution and 1 ml oftriethylamine, and heated at reflux for 3 hours. After allowing it tocool down, condensation under reduced pressure and addition with ethanolwere carried out for filtrating solid. It was washed with ether toobtain 105 mg of the title compound (108) (yield: 58%).

Slightly yellowish powder:

Melting point: >210° C. (decomp.)

¹ H-NMR(DMSO-d₆): 1.27 (d, J=6.4Hz, 3H), 2.91 (s, 3H), 3.09-3.28 (m,4H), 3.29-3.57 (m, 7H), 7.95 (d, J=12.7Hz, 1H), 8.77(s, 1H)

(2)-(11):

General procedures of Example 19 (1) were followed. Compounds(109)-(118) in Tables 22 to 23 were obtained.

                                      TABLE 22                                    __________________________________________________________________________     ##STR112##                                                                   Ex- Com-                  Melting                                             ample                                                                             pound                 point                          Preparing            No. No. Y           Property                                                                            (°C.)                                                                       .sup.1 H-NMR              method               __________________________________________________________________________    19(2)                                                                             109                                                                                ##STR113## Slightly yellowish powder                                                           168-172 decomp.                                                                    DMSO-d.sub.6 2.22, 2.37(each brs, each                                        1H), 2.88, 2.91(each s, each                                                  3H), 3.19-3.61(m, 6H), 3.66-3.92(m, 2H),                                      4.39, 4.62(each brs, each 1H), 7.89(d,                                        J=13.5Hz, 1H), 8.69(s, 1H)                                                                              method F             19(3)                                                                             110                                                                                ##STR114## Slightly yellowish powder                                                           228-230 decomp.                                                                    DMSO-d.sub.6 2.90(s, 3H), 2.98-3.41(m,                                        9H), 3.47(brs, 2H), 4.42(d, J=47.4Hz, 2H),                                    7.91(d, J=12.5Hz, 1H), 8.74(s,                                                                          method F             19(4)                                                                             111                                                                                ##STR115## Slightly yellowish powder                                                           221-223 decomp.                                                                    DMSO-d.sub.6 2.90(s, 3H), 2.98-3.41(m,                                        9H), 3.47(brs, 2H), 4.42(d, J=47.4Hz, 2H),                                    7.91(d, J=12.5Hz, 1H), 8.74(s,                                                                          method F             19(5)                                                                             112                                                                                ##STR116## Yellowish powder                                                                    >210 decomp.                                                                       DMSO-d.sub.6 2.89(s, 3H), 2.98-3.64(m,                                        11H), 3.65-3.83(m, 1H), 3.84-4.07(m, 1H),                                     7.94(d, J=16.2Hz, 1H), 8.21(brs, 1H),                                         8.78(s, 1H)               method F             19(6)                                                                             113                                                                                ##STR117## Slightly yellowish powder                                                           >195 decomp.                                                                       DMSO-d.sub.6 1.41(brs, 1H), 1.77(brs, 3H),                                    2.06-2.48(m, 2H), 2.93(s, 3H), 3.07(brs,                                      5H), 3.19-3.57(m, 6H), 7.92(d, J=13.5Hz,                                      1H), 8.73(s, 1H)          method               __________________________________________________________________________                                                             F                

                                      TABLE 23                                    __________________________________________________________________________     ##STR118##                                                                   Ex- Com-                   Melting                                            ample                                                                             pound                  point                         Preparing            No. No. Y            Property                                                                            (°C.)                                                                       .sup.1 H-NMR             method               __________________________________________________________________________    19(7)                                                                             114                                                                                ##STR119##  Slightly yellowish powder                                                           >210 decomp.                                                                       CDCl.sub.3 0.45-0.56(m, 4H), 1.68-1.78(m,                                     1H), 2.78(brs, 4H), 2.91(s, 3H), 3.10(t,                                      J=5.9Hz, 2H), 3.24(brs, 4H), 3.48(t,                                          J=5.9Hz, 2H), 8.02(d, J=12.2Hz, 1H),                                          8.82(s, 1H)              method F             19(8)                                                                             115                                                                                ##STR120##  Yellowish powder                                                                    >210 decomp.                                                                       DMSO-d.sub.6 1.27(d, J=6.4Hz, 3H),                                            2.91(s, 3H), 3.09-3.28(m, 4H),                                                3.29-3.57(m, 7H), 7.95(d, J=12.7Hz, 1H),                                      8.77(s, 1H)              method F             19(9)                                                                             116                                                                                ##STR121##  Slightly yellowish powder                                                           >215 decomp.                                                                       DMSO-d.sub.6 1.37(s, 6H), 2.90(s, 3H),                                        3.14(brs, 2H), 3.21(brs, 4H), 3.49(brs,                                       2H), 7.96(d, J=12.7Hz, 1H), 8.77(s,                                                                    method F              19(10)                                                                           117                                                                                ##STR122##  Colorless powder                                                                    >225 decomp.                                                                       DMSO-d.sub.6 2.24(brs, 4H), 2.75(s, 3H),                                      2.89(s, 3H), 3.21(brs, 2H), 3.51(brs,                                         2H), 3.60-3.75(m, 2H), 3.97(brs, 2H),                                         7.98(d, J=12.2Hz, 1H), 8.79(s,                                                                         method F              19(11)                                                                           118                                                                                ##STR123##  Yellowish powder                                                                    >194 decomp.                                                                       DMSO-d.sub.6 2.68-2.78(m, 1H), 2.89(s,                                        3H), 3.01-4.13 (m, 11H), 4.67-5.09(m,                                         1H), 7.94(d, J=13.5Hz, 1H), 8.78(s,                                                                    method               __________________________________________________________________________                                                             F                

EXAMPLE 20

5-Fluoro-4-(pyrrolidin-1-yl)-2,3-dihydro-1-formyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid (119):

315 mg of compound (102) obtained in Example 4 (21) was added to 1.17 gof formic acid and heated at 100° C. for 4 hours. After allowing it tocool down, 10 ml of ether was added thereto and stirred over 5 minutes.Solid matters produced were filtered out and washed with ether. 250 mgof a title compound (119) was obtained.

Slightly-brown needles

Melting point: 238°-243° C.

¹ H-NMR(DMSO-d₆): 1.91 (brs, 4H), 2.83-3.15 (m, 2H), 3.49 (s, 4H),3.65-3.85 (m, 1H), 7.83 (d, J=13.9Hz, 1H), 8.57 (s, 1H), 8.65 (s, 1H)

EXAMPLE 21

1-Acetyl-5-fluoro-4-(pyrrolidin-1-yl)-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid (120):

100 mg of compound (102) obtained in Example 4 (21) was dissolved in 1ml of acetic acid and 1 ml of acetic anhydride, and heated at 110° C.for 3 hours. The mixture was allowed to cool down. Produced solidmatters were filtered out and washed with ether. 80 mg of a titlecompound (120) was obtained.

Slightly-brown powder:

Melting point: 278°-283° C.

¹ H-NMR(DMSO-d₆): 1.90 (brs, 4H), 2.38 (s, 3H), 2.80-3.90 (m, 8H), 7.80(d, J=14.OHz, 1H), 8.57 (s,1H)

EXAMPLE 22

Methyl 4-(cis-3-amino-4-methylpyrrolidine-1-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(121):

2 ml of thionyl chloride was added to 20 ml of methanol while cooling onice, and then this solution was stirred at room temperature. 358 mg ofthe compound (30) obtained in Example 5 was added to the solvent, andthe solution was heated at reflux for 8 hours. The solvent was removedand 40 ml of chloroform and 20 ml of water were added to the residue.The solution was alkalized with sodium hydrogen carbonate, and theorganic layer was dried over magnesium sulfate. The solvent was removedby distillation. To the residue, ether was added and then ethyl acetatewas added to form crystals. They were filtered off and washed with ethylacetate in this order to obtain 270 mg of a title compound (121) (yield:72%).

Colorless needles:

Melting point: 199°-202° C. (decomp.)

¹ H-NMR (CDCl₃): 1.13 (d, J=6.9 Hz, 3H), 1.74 (brs, 2H), 2.36-2.48 (m,1H), 2.82-3.06 (m, 2H), 2.87 (s, 3H), 3.20-3.57 (m, 6H), 3.80-3.97 (m,1H), 3.91 (s, 3H), 7.96 (d, J=13.9 Hz, 1H), 8.56 (s, 1H)

EXAMPLE 23

Methyl4-(Pyrrolidin-1-yl)-S-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylate(122):

2.92 g of the compound (6) obtained in Example 2 (1), 1.07 g ofpyrrolidine and 2.25 g of 1,8-diazabicyclo[5.4.0]-7-undecene were addedto 20 ml of N,N-dimethylformamide, and the solution was heated at 80° C.for 12 hours. The solvent was removed by distillation, and 100 ml ofchloroform was added to the residue. After washing with water, theorganic layer was separated from the solution. After drying overmagnesium sulfate, the solvent was removed by distillation. To theresidue, 50 ml of isopropyl ether was added, and the solid was filteredto obtain 2.60 g of the subject compound (122).

Slightly yellowish powder:

Melting point: 203°-206° C.

¹ H-NMR (CDCl₃): 1.99 (s, 4H), 2.87 (s, 3H), 2.95 (brs, 2H), 3.30-3.55(m, 6H), 3.92 (s, 3H), 7.99 (d, J=14.0 Hz, 1H), 8.57 (s, 1H)

REFERENCE EXAMPLE 5

4-t-Butylamino-3-fluoro-2-(2-hydroxyethyl)nitrobenzene (123):

30.5 g (150 mmol) of 3,4-difluoro-2-(2-hydroxyethyl)nitrobenzene and 90ml (900 mmol) of t-butylamine were added to 150 ml of dimethylsulfoxideand 25 ml of toluene, and the solution was heated at reflux for 8.5hours. After air-cooling, the solution was poured into 1500 ml of water,and the deposited crystals were filtered. They were dissolved in 500 mlof chloroform, and after drying over magnesium sulfate, the solvent wasremoved by distillation. The residue was crystallized with n-hexane, andthe crystals were filtered off to obtain 35.5 g of the subject compound(123) in a 93% yield.

REFERENCE EXAMPLE 6

4-Amino-3-fluoro-2-(2-hydroxyethyl)nitrobenzene (124):

11 g of the compound (123) obtained in Comparative Example 5 was addedto 200 ml of concentrated hydrochloric acid, and the solution heated atreflux for 2.5 hours. After air-cooling, the solution was extracted with500 ml of ethyl acetate four times, and the extract was washed withaqueous 10% sodium hydrogen carbonate solution. After drying overmagnesium sulfate, the solvent was removed by distillation. The residuewas crystallized with n-hexane, and the crystals were filtered to obtain8.33 g of the subject compound (124) in a 97% yield.

REFERENCE EXAMPLE 7

4-Chloro-3-fluoro-2-(2-hydroxyethyl)nitrobenzene (125):

7.33 g (37 mmol) of the compound (124) obtained in Reference Example 6was added to 60 ml of 6N hydrochloric acid, and while cooling on ice, 15ml of aqueous solution containing 2.95 g (43 mmol) of sodium nitrite wasdropped to the solution through 5 minutes. The solution was stirred for30 minutes as was. Then, 20 ml of concentrated hydrochloric acid and 20ml of acetic acid were added to the solution, and the solution wasstirred for 1 hour. While cooling on ice, 35 ml of concentratedhydrochloric acid solution containing 6.20 g (63 mmol) of cuprouschloride was dropped to the solution through 40 minutes, and thesolution was stirred for 3 hours as was. The solution was extracted with300 ml of ethyl acetate, and after drying over magnesium sulfate, thesolvent was removed by distillation. The residue was separated by thecolumn chromatography (silica gel 100 g, eluent solvent;chloroform:methanol=50:1) to obtain 6.69 g of the subject compound (125)in a 83% yield.

REFERENCE EXAMPLE 8

4-Chloro-3-fluoro-2-(2-hydroxyethyl)aniline (126):

4.8 g of iron powder and 0.45 ml of concentrated hydrochloric acid wereadded to a mixture solvent of 50 ml of water and 10 ml of ethanol, andthe solution was heated at 80°-90° C. 6.69 g (31 mmol) of4-chloro-3-fluoro-2-(2-hydroxyethyl)nitrobenzene was added to thesolution through 10 minutes, and the solution was heated for 1 hour aswas. After air-cooling, 100 ml of ethyl acetate was added to thesolution, and insoluble matter was filtered. The organic layer wasseparated and was washed with aqueous 10% sodium hydrogen carbonatesolution. After drying over magnesium sulfate, the solvent was removedby distillation to obtain 4.68 g of the subject compound (126) in a 80%yield.

REFERENCE EXAMPLE 9

Diethyl {4-Chloro-3-fluoro-2-(2-hydroxyethyl)anilino}-methylenemalonate(127):

To 4.68 g (25 mmol) of the compound (126) obtained above, 5.36 (25 mmol)of diethyl ethoxymethylenemalonate was added, and the solution washeated at 120° C. for 2 hours. Then, ethanol was removed from thesolution by distillation, and crystals obtained were dispersed inn-hexane and filtered to obtain 8.55 g of the subject compound (127) ina 95% yield.

REFERENCE EXAMPLE 10

Diethyl{4-Chloro-3-fluoro-2-(2-t-butyldimethylsilyloxyethyl)anilino}methylenemalonate(128):

8.55 g (24 mmol) of the compound (127) obtained above and 1.70 g (25mmol) of imidazole were added to 50 ml of methylene chloride, and 10 mlof methylene chloride solution containing 3.77 g (25 mmol) oft-butyldimethylchlorosilane was dropped to the solution through 10minutes. After the solution was stirred at room temperature for 1 hour,0.30 g of imidazole and 0.67 g of t-butyldimethylchlorosilane werefurther added to the solution, and the solution was stirred for 1 hour.The solution was washed with 50 ml of water, and after drying overmagnesium sulfate, the solvent was removed by distillation. The residuewas separated by the column chromatography (silica gel 200 g, eluentsolvent; chloroform) to obtain 9.35 g of the oily subject compound (128)in a 82% yield.

REFERENCE EXAMPLE 11

Ethyl6-Chloro-7-fluoro-8-(2-t-butyldimethylsilyloxyethyl)-4-hydroxyquinoline-3-carboxylate(129):

To 8.35 g (17.1 mmol) of the compound (128), 80 ml of Dowtherm A(Trademark) was added, and the solution was heated until a fraction of200° C. was taken out. The solution was further heated at reflux for 5minutes. After air-cooling, 50 ml of ether was added to the solution,and the crystals were filtered off to obtain 5.62 g of the subjectcompound (129) in a 74% yield.

REFERENCE EXAMPLE 12

Ethyl6-Chloro-7-fluoro-8-(2-hydroxyethyl)-4-hydroxyquinoline-3-carboxylate(130): 5.62 g (13 mmol) of the compound (129) obtained above was addedin a mixture solvent of 100 ml of chloroform and 100 ml of methanol, and15 ml of 4N hydrochloric acid solution in dioxane was added to thesolution. After stirring at room temperature for 30 minutes, the solventwas removed from the solution by distillation. Crystals obtained weredispersed in ethanol and filtrated. They were washed with ethanol andether in this order to obtain 3.70 g of the subject compound (130) in a90% yield.

REFERENCE EXAMPLE 13

Ethyl1-Amino-6-chloro-7-fluoro-8-(2-hydroxyethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(131):

4 g (12.8 mmol) of the compound (130) obtained above and 3.53 g (25.6mmol) of anhydrous potassium carbonate were added to 70 ml ofdimethylformamide, and the solution was stirred at room temperature for2 hours. 7.29 g (25.5 mmol) of ethylo-(mesitylenesulfonyl)acetohydoxamate was added to 10 ml of dioxane, andwhile cooling on ice, 2.6 ml of 70% perchloric acid was dropped to thesolution below 10° C. through 15 minutes. The solution was stirred for20 minutes as was, and then added to 50. ml of ice/water. Crystals werefiltered off and washed on ice/water and then dissolved in 50 ml ofmethylene chloride. The organic layer was separated from the solution,and after drying over magnesium sulfate, while cooling on ice, thesolution was dropped to the previously prepared reaction solution ofdimethylformamide through 5 minutes. The solution was stirred for 1 houras was, and 100 ml of water was added to the solution. Crystals werefiltered off and washed with ethanol and ether in this order to obtain2.08 g of the subject compound (131) in a 50% yield.

EXAMPLE 24

Ethyl5-Chloro-4-fluoro-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(132):

2.08 g (6.3 mmol) of the compound (131) obtained in Reference Example 13and 2.62 g (10 mmol) of triphenylphosphine were added to 50 ml oftetrahydrofuran, and 50 ml of tetrahydrofuran solution containing 1.74 g(10 mmol) of diethyl azodicarboxylate was dropped to the solution atroom temperature through 2 hours. After 20 minutes, the solvent wasremoved by distillation. Solids obtained were dispersed in ethanol andfiltered off and washed with ethanol and ether in this order to obtain1.69 g of the subject compound (132) in a 86% yield.

Colorless powder:

Melting point: 235° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.0 Hz, 3H), 2.93 (brs, 2H), 3.41 (dt,J=6.2 Hz, 5.9 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 6.85 (t, J=6.9 Hz, 1H),8.09 (d, J=8.1 Hz, 1H), 8.42 (s, 1H)

EXAMPLE 25

Methyl5-Chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(133):

To 1.69 g (5.5 mmol) of the compound (132) obtained in Example 24, 10 ml(109 mmol) of dimethylsulfate was added, and the solution was heated at120° C. for 4.5 hours. After air-cooling, the solution was added to 90ml of ice/water to which 15 g (109 mmol) of anhydrous potassiumcarbonate was added, and the solution was stirred for 1 hour. Thesolution was extracted with 200 ml of chloroform, and after drying overmagnesium sulfate, the solvent was removed by distillation. The residuewas separated by the column chromatography (silica gel 60 g, eluentsolvent; chloroform methanol=100:1) to obtain 600 mg of the subjectcompound (133) in a 36% yield.

Slightly yellowish powder:

Melting point: 199° C. (decomp.)

¹ H-NMR (CDCl₃): 2.86 (s, 3H), 3.07 (t, J=5.8 Hz, 2H), 3.49 (t, J=5.9Hz, 2H), 3.92 (s, 3H), 8.42 (d, J=8.0 Hz, 1H), 8.60 (s, 1H)

EXAMPLE 26

5-Chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (134):

To 600 mg (1.9 mmol) of the compound (133) obtained in Example 25, 5 mlof concentrated hydrochloric acid and 20 ml of acetic acid were added,and the solution was heated at reflux for 2 hours. After air-cooling, 20ml of water was added to the solution, and solids were filtered off andwashed with ethanol and ether in this order to obtain 461 mg of thesubject compound (134) in a 80% yield.

Slightly yellowish powder:

Melting point: 223-225° C.

¹ H-NMR (DMSO-d₆): 2.88 (s, 3H), 3.11 (brs, 2H), 3.53 (t, J=5.5 Hz, 2H),8.33 (d, J=7.3 Hz, 1H), 8.83 (s, 1H)

EXAMPLE 27

5-Chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid BF₂ chelate (135):

300 mg (1 mmol) of the compound (134) obtained in Example 26 was addedto 6 ml of ether, and 9 ml of boron trifluoride--ether complex was addedto the solution. The solution was stirred at room temperature for 4hours. The deposited solids were filtered off and washed with ether toobtain the subject compound (135) in a 63% yield.

Colorless powder

Melting point: 275° C. (decomp.)

¹ H-NMR (DMSO-d₆): 3.01 (s, 3H), 3.23 (t, J=4.9 Hz, 2H), 3.63 (t, J=6.3Hz, 2H), 8.65 (d, J=7.8 Hz, 1H), 9.41 (s, 1H)

EXAMPLE 28

5-Chloro-4-(1-pyrrolidinyl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (136):

100 mg (0.29 mmol) of the compound (135) obtained in Example 27 was 0.5ml of dimethylsulfoxide, and 55 mg (0.64 mmol) of pyrrolidine was addedto the solution. The solution was stirred for 24 hours at roomtemperature. Then, 1 ml of ether and 2 ml of ethanol were added to thesolution to crystallize. Crystals were filtered off and washed withethanol and ether in this order to obtain 80 mg of the crystals. To theobtained crystals, 5 ml of 80% methanol and 0.5 ml of triethylamine wereadded, and the solution was heated at reflux for 4 hours. After thesolvent was removed by distillation, the crystals were dispersed inethanol and filtered off and were washed with ethanol and ether in thisorder to obtain 55 mg of the subject compound (136) in a 52% yield.

Slightly yellowish prisms:

Melting point: 244° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.00 (brs, 4H), 2.90 (s, 3H), 3.01 (brs, 2H), 3.41(brs, 4H), 3.47 (brs, 2H), 8.20 (s, 1H), 8,75 (s, 1H)

REFERENCE EXAMPLE 14

2-Chloro-6-nitrophenylacetic acid (137):

8.08 g (202 mmol) of 60% sodium hydride was added to 30 ml oftetrahydrofuran, and while cooling on a freezing mixture, 60 ml oftetrahydrofuran solution containing 32.0 g (200 mmol) of diethylmalonate was dropped to the solution below 20° C. over 1 hour, then thesolution was stirred for 1 hour. 60 ml of Tetrahydrofuran solutioncontaining 19.2 g (100 mmol) of 2,3-dichloronitrobenzene was dropped tothe solution below 10° C. over 10 minutes. After the solution wasstirred for 3.5 hours at room temperature, it was heated at reflux for48 hours. 18 ml of acetic acid was added to the solution, and thesolvent was removed by distillation. The solution was extracted over 200ml of chloroform, and after drying over magnesium sulfate, the solventwas removed by distillation. To the residue, 30 ml of 4N hydrochloricacid and 25 ml of acetic acid were added, and the solution was heated atreflux for 24 hours. After air-cooling, the deposited crystals werefiltered off and washed with water, and they were dissolved in 250 ml ofethyl acetate. The filtrate was extracted with 250 ml of ethyl acetate.The organic layers were combined, and after drying over magnesiumsulfate, the solvent was removed by distillation. The crystals werewashed with n-hexane to obtain 6.78 g of the subject compound (137) in a31% yield.

REFERENCE EXAMPLE 15

3-Chloro-2-(2-hydroxyethyl)nitrobenzene (138):

2.26 g (59.8 mmol) of sodium borohydride was added to 7 ml oftetrahydrofuran, and while cooling on ice, 15 ml of tetrahydrofuransolution containing 6.78 g (31.5 mmol) of the compound (137) obtainedabove was dropped to the solution through 20 minutes. Then, 15 ml oftetrahydrofuran solution containing 10 ml of borontrifluoride--ethercomplex was dropped to the solution through 10 minutes, and afterstirring for 30 minutes as was, the solution was stirred for 1 hour atroom temperature. To 130 ml of water containing 9.6 g of sodium hydrogencarbonate and 170 ml of methylene chloride, the reaction solution wasadded slowly, and the obtained solution was stirred overnight at roomtemperature. The organic layer was separated, and after drying overmagnesium sulfate, the solvent was removed by distillation. To theresidue, n-hexane was added to crystallize, and the crystals werefiltered off and washed with n-hexane to obtain 5.43 g of the subjectcompound (138) in a 86% yield.

REFERENCE EXAMPLE 16

3-Chloro-2-(2-hydroxyethyl)aniline (139):

4.5 g of iron powder and 0.45 ml of concentrated hydrochloric acid wereadded to a mixture solvent of 50 ml of water and 10 ml of ethanol, andthe solution was heated at 80°-90° C. 5.43 g of the compound (138)obtained above was added to the solution through 10 minutes, and thesolution was heated for 30 minutes as was. After air-cooling, 100 ml ofethyl acetate was added to the solution, and insoluble matter wasfiltered. The organic layer was separated from the solution and waswashed with 10% sodium hydrogen carbonate solution, and after dryingover magnesium sulfate, the solvent was removed by distillation. Thecrystals obtained were washed with n-hexane to obtain 4.40 g of thesubject compound (139) in a 95% yield.

REFERENCE EXAMPLE 17

Diethyl {3-Chloro-2-(2-hydroxyethyl)anilinoymethylene malonate (140):

To 4.40 g (25.6 mmol) of the compound (139) obtained above, 5.55 g (25.6mmol) of diethyl ethoxymethylenemalonate was added, and the solution washeated at 120° C. for 4 hours. After air-cooling, crystals weredispersed in n-hexane and filtered off to obtain 8.52 g of the subjectcompound (140) in a 97% yield.

REFERENCE EXAMPLE 18

Diethyl {3-Chloro-2-(2-t-butyldimethylsilyloxyethyl)anilino]methylenemalonate (141): 8.52 g (25 mmol) of the compound (140) and 1.77 (26mmol) of imidazole were added to 50 ml of methylene chloride, and 10 mlof methylene chloride containing 3.92 g (26 mmol) oft-butyldimethylehlorosilane was dropped to the solution through 10minutes. The solution was stirred for 1 hour at room temperature. 0.30 gof imidazole and 0.67 g of t-butyldimethylchlorosilane were supplementedto the solution, and the solution was stirred for 1 hour. The solutionwas washed with 50 ml of water, and after drying over magnesium sulfate,the solvent was removed by distillation. The solid matter was separatedby column chromatography (silica gel 200 g, eluent solvent; chloroform)to obtain 11.5 g of oily subject compound (141).

REFERENCE EXAMPLE 19

Ethyl 7-Chloro-8-(2-hydroxyethyl)-4-hydroxyquinoline-3-carboxylate(142):

To 11 g of the compound (141) obtained above, 80 ml of Dowtherm A(Trademark) was added, and the solution was heated until a fraction of200° C. was taken out. Further, the solution was heated at reflux for 20minutes. After air-cooling, 10 ml of concentrated hydrochloric acid wasadded to the solution. After stirring for 30 minutes at roomtemperature, the deposited crystals were filtered off and washed withethanol and ether in this order to obtain 4.96 g of the subject compound(142) in a 70% yield.

REFERENCE EXAMPLE 20

Ethyl1-Amino-7-chloro-8-(2-hydroxyethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(143):

4.96 g (16.8 mmol) of the compound (140) obtained above and 4.65 g ofanhydrous potassium carbonate were added to 90 ml ofN,N-dimethylformamide, and the solution was stirred for 2 hours at roomtemperature. 9.60 g of ethyl o-(mesitylene-sulfonyl)acetohydroxamate wasadded to 13 ml of dioxane, and while cooling on ice, 3.4 ml of 70%perchloric acid was dropped below 10° C. through 15 minutes. Thesolution was stirred for 20 minutes as was, and added to 50 ml ofice/water. Crystals were filtered off and washed with ice/water anddissolved in 50 ml of methylene chloride. The organic layer wasseparated and was dropped to the previously prepared reaction solutionof the dimethylformamide through 5 minutes, while cooling on ice, afterdrying over magnesium sulfate. The solution was stirred for 1 hour aswas, and 100 ml of water was added to the solution. Crystals werefiltered off and washed with ethanol and ether in this order to obtain0.69 g of the subject compound (143) in a 13% yield.

EXAMPLE 29

Ethyl4-Chloro-2,3-dihydro-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylate(144):

1.02 g (3.3 mmol) of the compound (143) obtained in Reference Example 20and 1.37 g (5.2 mmol) of triphenylphosphine were added to 25 ml oftetrahydrofuran, and 25 ml of tetrahydrofuran solution containing 0.91 g(5.2 mmol) of diethyl azodicarboxylate was dropped to the solution atroom temperature through 1 hour. After 20 minutes, the solvent wasremoved by distillation. The solids obtained were dispersed in ethanoland filtered off and then washed with ethanol and ether in this order toobtain 0.81 g of the subject compound (144) in a 84% yield.

Colorless powder:

Melting point: 210.5°-213° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.27 (t, J=7.3 Hz, 3H), 2.93 (t, J=5.9Hz, 2H), 3.44(dt, J=2.9 Hz, 6.2 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 6.84 (t, J=7.3 Hz,1H), 7.55 (d, J=8.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 8.44 (s, 1H)

EXAMPLE 30

Methyl4-Chloro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylate(145):

To 810 mg (2.8 mmol) of the compound (144) obtained in Example 29, 5 ml(55 mmol) of dimethyl sulfate was added, and the solution was heated forat 120° C. for 5.5 hours. After air-cooling, to 45 ml of ice/watercontaining 7.5 g (55 mmol) of anhydrous potassium carbonate, was addedthe solution, and was stirred for 1 hour. The solution was extractedwith 50 ml of chloroform, and after drying over magnesium sulfate, thesolvent was removed by distillation. The residue was separated by thecolumn chromatography (silica gel 8 g, eluent solvent;chloroform:methanol=100:1) to obtain 371 mg of the subject compound(145) in a 46% yield.

Colorless powder:

Melting point: 225° C. (decomp.)

¹ H-NMR (CDCl₃): 2.85 (s, 3H), 3.09 (t, J=6.2 Hz, 2H), 3.51 (t, J=5.9Hz, 2H), 3.93 (s, 3H), 7.45, 8.33 (each d, each J=8.8 Hz, each 1H), 8.62(s, 1H)

EXAMPLE 31

4-Chloro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (146):

To 370 mg (1.3 mmol) of the compound (145) obtained in Example 30, 2 mlof concentrated hydrochloric acid and 10 ml of acetic acid were added,and the solution was heated at reflux for 2 hours. The solvent wasremoved by distillation. Crystals were dispersed in ethanol and filteredand washed with ethanol and ether in this order to obtain 270 mg of thesubject compound (146) in a 77% yield.

Colorless prisms:

Melting point:>240° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.88 (s, 3H), 3.10, 3.57 (each brs, each 2H), 7.77,8.25 (each d, each J=8.4 Hz, each 1H), 8.81 (s, 1H)

EXAMPLE 32

4-Chloro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylicacid BF2 chelate (147):

240 mg (0.86 mmol) of the compound (146) obtained in Example 31 wasadded to 6 ml of ether, and 9 ml of borontrifluoride-ether complex wasadded to the solution. The solution was stirred overnight at roomtemperature. The deposited crystals were filtered off and washed onether to obtain 266 mg of the subject compound (147) in a 94% yield.

Colorless powder:

Melting point: >285° C. (decomp.)

¹ H-NMR (DMSO-d₆): 3.02 (s, 3H), 3.23, 3.67 (each brs, each 2H), 8.06,8.46 (each d, each J=9.4 Hz, each 1H), 9.37 (s, 1H)

REFERENCE EXAMPLE 21

3,4-Difluoro-2-(2-oxopropyl)nitrobenzene (148):

12.1 g (303 mmol) of 60% sodium hydride was added to 45 ml oftetrahydrofuran, and while cooling with a freezing mixture, 90 ml oftetrahydrofuran containing 39.0 g (300 mmol) of ethyl acetoacetate wasdropped to the solution below 20° C. through 30 minutes. After thesolution was stirred for 1 hour as was, 90 ml of tetrahydrofuransolution containing 26.6 g (150 mmol) of 2,3,4-trifluoronitrobenzene wasdropped to the solution below 10° C. through 30 minutes, and thesolution was stirred overnight at room temperature. 27 ml of acetic acidwas added to the solution, and the solvent was removed by distillation.The solution was extracted with 500 ml of chloroform, and after dryingover magnesium sulfate, the solvent was removed by distillation. 30 mlof 4N hydrochloric acid and 25 ml of acetic acid were added to thesolution, and the solution was heated at reflux for 24 hours. 550 ml ofconcentrated hydrochloric acid and 550 ml of acetic acid were added tothe solution, and the solution was heated at reflux for 16 hours. Afterair-cooling, the solution was extracted with 1 l of chloroform and waswashed with 500 ml of water two times. The solution was further washedwith 300 ml of aqueous saturated sodium hydrogen carbonate solution twotimes, and after drying over magnesium sulfate, the solvent was removedby distillation. The residue was separated by the column chromatography(silica gel 300 g, eluent solvent; chloroform: n-hexane=1 :3) to obtain31.2 g of the subject compound (148) in a 90% yield.

REFERENCE EXAMPLE 22

3,4-Difluoro-2-(2-hydroxypropyl)nitrobenzene (149):

31.2 g (145 mmol) of the compound (148) obtained above was added to 500ml of methanol, and while cooling on ice, 6.04 g (160 mmol) of sodiumborohydride was added to the solution through 5 minutes. After thesolution was stirred for 30 minutes as was, the solution was stirredovernight at room temperature. 100 ml of 4N hydrochloric acid was addedslowly to the solution and the solution was stirred for 30 minutes atroom temperature. Then, the solvent was removed by distillation. Thesolution was extracted with 400 ml of chloroform, and after drying overmagnesium sulfate, the solvent was removed by distillation to obtain27.7 g of the subject compound (149) in a 89% yield.

REFERENCE EXAMPLE 23

3,4-Difluoro-2-(2-hydroxypropyl)aniline (150):

23 g of iron powder and 2.3 ml of concentrated hydrochloric acid wereadded to a mixture solvent of 250 ml of water and 50 ml of ethanol, andthe solution was heated at 80°-90° C. 27.7 g (128 mmol) of the compound(149) obtained above was added to the solution through 30 minutes, andthe solution was heated for 40 minutes as was. After air-cooling, 200 mlof ethyl acetate was added to the solution, and insoluble matter wasfiltered. The organic layer was separated and the aqueous solution wasextracted with 200 ml of ethyl acetate. The organic layers were combinedand after drying over magnesium sulfate, the solvent was removed bydistillation to obtain 21.1 g of the subject compound (150) in a 89%yield.

REFERENCE EXAMPLE 24

Diethyl {3,4-Difluoro-2-(2-hydroxypropyl)anilino}-methylenemalonate(151):

To 21.1 g (113 mmol) of the compound (150) obtained above, 24.4 g (113mmol) of diethyl ethoxymethylenemalonate was added, and the solution washeated at 120° C. for 3 hours. After air-cooling, crystals depositedwere dispersed in n-hexane and filtered off to obtain 25.0 g of thesubject compound (151) in a 62% yield.

REFERENCE EXAMPLE 25

Diethyl{3,4-Difluoro-2-(2-t-butyldimethylsilyloxypropyl)anilino}methylenemalonate(152):

14.2 g (40 mmol) of the compound (151) and 3.27 g (48 mmol) of imidazolewere added to 100 ml of methylene chloride, and 20 ml of methylenechloride containing 7.23 g (48 mmol) of t-butyldimethylchlorosilane wasdropped to the solution through 30 minutes. After the solution wasstirred for 2.5 hours at room temperature, it was heated at reflux for 2hours. 3.27 g of imidazole and 7.23 g of t-butyldimethylehlorosilanewere supplemented to the solution, and the solution was heated at refluxfor 11 hours. The solution was washed 100 ml of water, 50 ml of aqueous5% citric acid solution and 50 ml of saturated aqueous sodium hydrogencarbonate solution in this order, and after drying over magnesiumsulfate, the solvent was removed by distillation. The solid matter wasseparated by column chromatography (silica gel 600 g, eluent solvent;chloroform:n-hexane=1:1) to obtain 14.2 g of an oily subject compound(152) in a 76% yield.

REFERENCE EXAMPLE 26

Ethyl 6,7-Difluoro-8-(2-hydroxypropyl)-4-hydroxyquinoline-3-carboxylate(153):

To 14.2 g (30 mmol) g of the compound (152) obtained above, 130 ml ofDowtherm A (Trademark) was added, and the solution was heated until afraction of 200° C. was taken out. Further, the solution was heated atreflux for 20 minutes. After air-cooling, 15 ml of concentratedhydrochloric acid was added to the solution. After stirring for 1.5hours at room temperature, deposited crystals were filtered off andwashed with ethanol and ether in this order to obtain 5.32 g of thesubject compound (153) in a 57% yield.

REFERENCE EXAMPLE 27

Ethyl 1-Amino-6,7-difluoro-8-(2-hydroxypropyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (154):

2.40 g (7.7 mmol) of the compound (153) obtained above and 2.13 g (15.4mmol) of anhydrous potassium carbonate were added to 50 ml ofdimethylformamide, and the solution was stirred for 4 hours at roomtemperature. 6.58 g (23.1 mmol) of ethylo-(mesitylene-sulfonyl)acetohydroxamate was added to 10 ml of dioxane,and while cooling on ice, 2.5 ml of 70% perchloric acid was droppedbelow 10° C. through 15 minutes. The solution was stirred for 20minutes, and was added to 50 ml of ice/water. Crystals were filtered offand washed with ice/water and was dissolved in 50 ml of methylenechloride. The organic layer was separated and was dropped to thepreviously prepared reaction solution of the dimethylformamide through 5minutes, while cooling on ice, after drying over magnesium sulfate. Thesolution was stirred for 1 hour, and 100 ml of water was added to thesolution. Crystals were filtered off and washed with water, ethanol andether in this order to obtain 1.00 g of the subject compound (154) in a40% yield.

EXAMPLE 33

Ethyl4,5-Difluoro-2-methyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(155):

2.35 g (7.2 mmol) of the compound (154) obtained in Reference Example 27and 2.98 g (11.3 mmol) of triphenylphosphine were added to 50 ml oftetrahydrofuran, and 50 ml of tetrahydrofuran solution containing 1.97 g(11.3 mmol) of diethyl azodicarboxylate was dropped to the solution atroom temperature through 2 hours. After 20 minutes, the solvent wasremoved by distillation. Solids were dispersed to ethanol and filteredoff and washed with ethanol and ether in this order to obtain 1.45 g ofthe subject compound (155) in a 65% yield.

Colorless powder:

Melting point: 226°-230° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.25 (t, J=5.9 Hz, 3H), 1.29 (t, J=7.0 Hz, 3H), 2.61(dd, J=8.4 Hz, 17.0 Hz, 1H), 3.12 (q, J=16.8 Hz, 1H), 3.27-3.51 (m, 1H),4.20 (q, J=7.0 Hz, 2H), 6.77 (d, J=9.9 Hz, 1H), 7.90 (dd, J=10.2 Hz,10.2 Hz, 1H), 8.44 (s, 1H)

EXAMPLE 34

Methyl4,5-Difluoro-2,3-dihydro-1,2-dimethyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(156):

To 1.45 g (4.7 mmol) of the compound (155) obtained in Example 33, 10 ml(109 mmol) of dimethyl sulfate was added, and the solution was heated3.5 hours at 120° C. After air-cooling, to 90 ml of ice/water containing15 g (109 mmol) of anhydrous potassium carbonate, the solution wasadded, and the solution was stirred overnight. The solution wasextracted with 50 ml of chloroform, and after drying over magnesiumsulfate, the solvent was removed by distillation. The residue wasseparated by column chromatography (silica gel 8 g, eluent solvent;chloroform:methanol=100:1) to obtain 830 mg of the subject compound(156) in a 57% yield.

Colorless powder:

Melting point: 184°-185° C.

¹ H-NMR (CDCl₃): 1.27 (d, J=6.9 Hz, 3H), 2.77 (s, 3H), 2.82 (dd, J=5.5Hz, 18.3 Hz, 1H), 3.16 (dd, J=5.1 Hz, 17.6 Hz, 1H), 3.93 (s, 3H),3.54-3.66 (m, 1H), 8.15 (dd, J=9.2 Hz, 9.2 Hz, 1H), 8.59 (s, 1H)

EXAMPLE 35

4,5-Difluoro-2,3-dihydro-1,2-dimethyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (157):

To 830 mg (2.7 mmol) of the compound (156) obtained in Example 34, 4 mlof concentrated hydrochloric acid and 16 ml of acetic acid were addedand the solution was heated at reflux for 3 hours. 10 ml of water wasadded to the solution. Solids were filtered off and washed with ethanoland ether in this order to obtain 700 mg of the subject compound (157)in a 88% yield.

Colorless powder:

Melting point: 270°-271° C.

¹ H-NMR (DMSO-d₆): 1.13 (d, J=7.0 Hz, 3H), 2.80 (s, 3H), 2.91 (dd, J=5.1Hz, 18.5 Hz, 1H), 3.25 (dd, J=4.8 Hz, 18.1 Hz, 1H), 3.71-3.78 (m, 1H),8.19 (dd, J=8.4 Hz, 8.4 Hz, 1H), 8.79 (s, 1H)

EXAMPLE 36

5-Fluoro-4-1(cis(-)-3-amino-4-methylpyrrolidin)-1-yl}-2,3-dihydro-1,2α,β-dimethyl-7-oxo-1H,7H-pyrido-[3,2,1-ij]cinnoline-8-carboxylicacid (158):

100 mg (0.34 mmol) of the compound (157) obtained in Example 35, 118 mg(0.68 mmol) of cis (-)-3-amino-4-methylpyrrolidine dihydrochloride and310 mg (2.04 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 1ml of acetonitrile, and the solution was heated at reflux for 3 hours.Then, the solvent was removed by distillation, and the solid matter wasextracted over 40 ml of chloroform. After drying over magnesium sulfate,the solvent was removed by distillation. The solid matter was dispersedin ethanol and ether and filtered off to obtain 80 mg of the subjectcompound (158) in a 64% yield.

Slightly brown powder:

Melting point: 228°-230° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.00-1.21 (m, 6H), 2.80-2.86 (m, 4H), 3.94-4.04 (m,1H), 7.84 (d, J=13.5 Hz, 1H), 8.64 (s, 1H)

EXAMPLE 37

5-Fluoro-4-{(3R)-((1'S)-aminoethyl)pyrrolidin)-1-yl}-2,3-dihydro-1,2α,β-dimethyl-7-oxo-1H,7H-pyrido[3,2,1-ij]-cinnoline-8-carboxylicacid Hydrochloride (159):

100 mg (0.34 mmol) of the compound (158) obtained in Example 36, 127 mg(0.68 mmol) of (3R)-((1'S)-aminoethyl)pyrrolidine dihydrochloride and310 mg (2.04 mmol) of 1,8-diazabicyclo[5,4,01-7-undecene were added to 1ml of acetonitrile, and the solution was heated at reflux for 3 hours.Then, the solvent was removed by distillation. 5 ml of ethanol and 1 mlconcentrated hydrochloric acid were added to the solid and the solventwas removed by distillation. The deposited solids were dispersed inethanol and filtered to obtain 10 mg of the subject compound (159) in a8% yield.

Yellowish powder:

Melting point: >210° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.01, 1.23 (each d, each J=8.1 Hz, each 1.5 H), 1.32(d, J=8.1 Hz, 3H) 1.67-1.79 (m, 1H), 2.10 (brs, 1H), 2.39-2.48 (m, 1H),2.79-3.00 (m, 4H), 3.30 (brs. 1H), 3.49-3.80 (m, 6H), 7.85 (d, J=13.5Hz, 1H), 8.30 (brs, 1H), 8.65 (s, 1H)

EXAMPLE 38

5-Fluoro-4-(pyrrolidin-1-yl)-2,3-dihydro-1,2-dimethyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (160):

100 mg (0.34 mmol) of the compound (157) obtained in Example 35 and 88mg (1.24 mmol) of pyrrolidine were added to 1 ml of acetonitrile, andthe solution was heated at reflux for 3 hours. Then, the solvent wasremoved by distillation, and the residue was extracted with 20 ml ofchloroform, and after drying over magnesium sulfate, the solvent wasremoved by distillation. The residue was solidified with ether and thesolids were filtered off to obtain 70 mg of the subject compound (160)in a 60% yield.

Colorless powder:

Melting point: 224°-225° C. (decomp.)

¹ H-NMR (CDCl₃): 1.19 (d, J=7.0 Hz, 3H), 2.01 (brs, 4H), 2.68 (dd, J=5.9Hz, 16.8 Hz, 1H), 2.82 (s, 3H), 3.01 (dd, J=5.1 Hz, 17.0 Hz, 1H), 3.52(brs, 5H), 7.97 (d, J=13.9 Hz, 1H), 8.77 (s, 1H)

EXAMPLE 39

(1) Ethyl5-Fluoro-4-{cyano(ethoxycarbonyl)methyl}-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylate(161):

168 mg (4.2 mmol) of 60% sodium hydride was added to 20 ml ofN,N-dimethylformamide, and while cooling on ice, 452 mg (4 mmol) ofethyl cyanoacetate was dropped to the solution. The solution was stirredfor 1 hour at room temperature. 612 mg (2 mmol) of ethyl4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylatewas added to the solution, and the solution was stirred overnight atroom temperature. The solution was heated at 70° C. for 2 hours, and thesolvent was removed by distillation. 80 ml of chloroform and 20 ml ofwater were added to the residue, and the solution was acidified withcitric acid. The organic layer was separated and after drying overmagnesium sulfate, the solvent was removed by distillation. The residuewas purified by column chromatography (silica gel 20 g, eluent solvent;ethyl acetate) to obtain 450 mg of the subject compound (161).

Colorless prisms:

Melting point:153°-154.5° C.

¹ H-NMR (CDCl₃): 1.33, 1.42 (each t, each J=7.0 Hz, each 3H), 2.87 (s,3H), 2.91-2.96, 3.27-3.39 (each m, each 1H), 3.55 (brs, 2H), 4.30-4.41(m, 4H), 5.35 (s, 1H), 8.18 (d, J=10.3 Hz, 1H), 8.62 (s, 1H)

(2) The following compound was obtained in the similar manner as Example39 (1).

Ethyl5-Fluoro-4-{cyano(t-butoxycarbonyl)methyl}-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylate(162):

Colorless needles:

Melting point:169°-170.5° C.

¹ H-NMR (CDCl₃): 1.41 (t, J=7.3 Hz, 3H), 1.50 (s, 9H), 2.87 (s, 3H),2.92-3.00, 3.29-3.40 (each m, each 1H), 3.55 (brs, 2H), 4.40 (q, J=6.9Hz, 2H), 5.27 (s, 1H), 8.17 (d, J=10.3 Hz, 1H), 8.62 (s, 1H)

EXAMPLE 40

8-Carboxy-5-fluoro-2,3-dihydro-1-methyl- 7-oxo-1H,7H-Pyrido[3,2,1-il]cinnoline-4-acetic acid (163):

To 450 mg of the compound (161) obtained in Example 39, 4 ml ofconcentrated hydrochloric acid and 16 ml of acetic acid were added, andthe solution was heated at reflux for 7.5 hours. The solvent was removedby distillation, and crystals were filtered off and washed with ethanoland ether in this order to obtain 124 mg of the subject compound (163).

Colorless prisms:

Melting point:215° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.85 (s, 3H), 3.09, 3.56, 3.92 (each brs, each 2H),7.95 (d, J=9.5 Hz, 1H), 8.78 (s, 1H)

EXAMPLE 41

5-Fluoro-1,4-dimethyl-2,3-dihydro-7-oxo-1H,7H-pyrido-[3,2,1-il]cinnoline-8-carboxylicacid (164):

100 mg of the compound (163) obtained in Example 40 and 1.4 ml oftriethylamine were added to 5 ml of ethanol, and the solution was heatedat reflux for 15.5 hours. After air-cooling, the solids were filteredand washed successively with ethanol and ether to obtain 65 mg of thesubject compound (164).

Colorless powder:

Melting point:>260° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.38, 2.86 (each s, each 3H), 3.07 (t, J=5.5 Hz, 2H),3.31 (t, J=3.3 Hz, 2H), 7.91 (d, J=9.5 Hz, 1H), 8.76 (s, 1H)

EXAMPLE 42

Ethyl4-Cyanomethyl-5-fluoro-1-methyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(165):

1.60 g of the compound (162) obtained in Example 39 (2) was added to 20ml of methylene chloride, and 6 ml of trifluoroacetic acid was added tothe solution. The solution was stirred for 1.5 hours. 4 ml oftrifluoroacetic acid was added to the solution, and the solution wasstirred overnight. The solvent was removed by distillation, and theresidue was crystallized from ethyl ether. Crystals were filtered off toobtain 410 mg of the subject compound (165).

Slightly brown powder:

Melting point:208.5°-210.5° C. (decomp.)

¹ H-NMR (CDCl₃): 1.42 (t, J=7.0 Hz, 3H), 2.88 (s, 3H), 3.13 (t, J=5.9Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 3.88 (s, 2H), 4.40 (q, J=7.0 Hz, 2H),8.11 (d, J=9.5 Hz, 1H), 8.61 (s, 1H) IR (KBr) 2250 cm⁻¹ (CN)

EXAMPLE 43

5-Fluoro-4-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (166):

2.78 g of the compound (8) obtained in Example 3 was added to 10 ml ofaqueous 30% potassium hydroxide solution, and the solution was heated atreflux for 6 hours. After air-cooling, the solution was acidified with6N hydrochloric acid, and the deposited solids were filtered off andwashed with water, ethanol and isopropyl ether in this order to obtain2.60 g of the subject compound (166).

Colorless powder:

Melting point: >290° C.

¹ H-NMR (DMSO-d₆): 2.84 (s, 3H), 2.94 (brs, 2H), 3.49 (brs, 2H), 7.90(d, J=11.0 Hz, 1H), 8.70 (s, 1H)

EXAMPLE 44

Methyl5-Fluoro-4-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(167):

To 100 ml of methanol, while cooling on ice, 9 ml of thionyl chloridewas added, and the solution was stirred for 30 minutes at the sametemperature. 2.60 g of the compound (166) obtained in Example 43 wasadded to the solution, and the solution was heated at reflux for 24hours. After air-cooling, insoluble matter was removed by filtering, andthe filtrate was removed by distillation. To the residue, chloroform wasadded, and the formed solid matter was filtered off to obtain 2.20 g ofthe subject compound (167).

Slightly yellowish powder:

Melting point: >290° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.78 (s, 3H), 2.90, 3.43 (each brs, each 2H), 3.74(s, 3H), 7.74 (d, J=11.4 Hz, 1H), 8.46 (s, 1H)

EXAMPLE 45

Methyl5-Fluoro-4-methanesulfonyloxy-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(168):

304 mg of the compound (167) obtained in Example 44 was added to 2 ml ofpyridine, and 120 mg of methane-sulfonyl chloride was added to thesolution. The solution was stirred for 3 hours at room temperature. 50ml of chloroform was added to the solution, and the solution was washedwith aqueous 5% citric acid solution. The organic layer was separated,and after drying over magnesium sulfate, the solvent was removed bydistillation. To the residue, ethanol was added, and the solid matterwas filtered off and washed with isopropyl ether to obtain 260 mg of thesubject compound (168).

Colorless powder:

Melting point: 247°-250° C.

¹ H-NMR (DMSO-d₆): 2.82 (s, 3H), 3.11, 3.48 (each brs, each 2H), 3.70,3.76 (each s, each 3H), 7.95 (d, J=10.3 Hz, 1H), 8.57 (s, 1H)

EXAMPLE 46

Methyl5-Fluoro-4-(4-methylphenylsulfonyloxy)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(169):

304 mg of the compound (168) obtained in Example 45 was added to 2 ml ofpyridine, and 260 mg of p-toluene-sulfonyl chloride was added to thesolution. The solution was stirred for 2 hours at room temperature. 50ml of chloroform was added to the solution, and the solution was washedwith water and aqueous 5% citric acid solution. The organic layer wasseparated, and after drying over magnesium sulfate, the solvent wasremoved by distillation. To the residue, ethanol was added, and thesolid matter was filtered off and washed with isopropyl ether to obtain220 mg of the subject compound (169).

Slightly yellowish powder:

Melting point: 182°-186° C.

¹ H-NMR (CDCl₃): 2.51 (s, 3H), 2.88 (s, 3H), 3.23, 3.47 (each t, eachJ=6.0 Hz, each 2H), 3.92 (s, 3H), 7.40, 7.86 (each d, each J=8.1 Hz,each 2H), 8.04 (d, J=9.9 Hz, 1H), 8.64 (s, 1H)

EXAMPLE 47

Methyl5-Fluoro-4-(trifluoromethanesulfonyloxy)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylate(170):

2.8 g of the compound (169) obtained in Example 46 was added to 10 ml ofpyridine, and while cooling on ice, 2.35 ml of trifluoromethanesulfonicanhydride was added to the solution through 20 minutes. The solution wasstirred for 24 hours at room temperature. 200 ml of chloroform was addedto the solution, and the solution was washed with aqueous 5% citric acidsolution. The organic layer was separated and after drying overmagnesium sulfate, the solvent was removed by distillation. To theresidue, ethanol was added, and the solid matter was filtered off andpurified by column chromatography (silica gel, eluent solvent;chloroform:ethyl acetate=1:1). The solid matter was filtered off andwashed with isopropyl ether to obtain 1.2 g of the subject compound(170).

Colorless powder:

Melting point: 170°-172° C.

¹ H-NMR (CDCl₃): 2.90 (s, 3H), 3.20, 3.55 (each t, each J=6.0 Hz, each2H), 3.95 (s, 3H), 8.25 (d, J=10.0 Hz, 1H), 8.65 (s, 1H)

EXAMPLE 48

Methyl5-Fluoro-4-(3-oxo-1-cyclohexen-1-yl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(171):

424 mg of the compound (170) obtained in Example 47, 404 mg of3-tributylstanyl-2-cyclohexen-1-one, 127 mg of lithium chloride and 14mg of bis(triphenylphosphine)palladium (11) chloride were added to 5 mlof tetrahydrofuran, and the solution was heated at reflux for three daysunder nitrogen. The solvent was removed by distillation. To the residue,n-hexane was added, and the solid matter was filtered off. The obtainedsolid matter was separated by column chromatography (silica gel, eluentsolvent; chloroform:ethyl acetate=8:1) to obtain 120 mg of the subjectcompound (171).

Slightly yellowish oily material:

¹ H-NMR (DMSO-d₆): 2.05-2.20 (m, 2H), 2.59 (s, 2H), 2.84 (s, 3H),2.85-3.03 (m, 2H), 3.44 (brs, 2H), 3.75 (s, 3H), 6.13 (s, 1H), 7.83 (d,J=10.0 Hz, 1H), 8.56 (s, 1H)

EXAMPLE 49

5-Fluoro-4-(3-oxo-1-cyclohexen-1-yl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (172):

120 mg of the compound (171) obtained in Example 48 was added to amixture solution of 3 ml of tetrahydrofuran, 1 ml of 6N hydrochloricacid and 1 ml of water, and the solution was stirred for four days atroom temperature. The deposited solid matter was filtered off and washedwith water and ethanol in this order to obtain 44 mg of the subjectcompound (172).

Colorless needles:

Melting point: >300° C.

¹ H-NMR (DMSO-d₆): 2.00-2.20 (m, 2H), 2.60 (brs, 2H), 2.91 (s, 3H), 3.05(brs, 2H), 3.45-3.55 (m, 2H), 6.17 (s, 1H), 8.01 (d, J=10.0 Hz, 1H),8.81 (s, 1H)

EXAMPLE 50

Ethyl3,4-Difluoro-1,2-dihydro-6-oxo-1H,6H-pyrido-[3,2,1-hilindazole-7-carboxylate(178):

1.29 g (4 mmol) of the compound (99) obtained in Example 16 was added to8 ml of a mixture solution of concentrated hydrochloric acid--aceticacid (at a ratio of 1:4 by volume), and the solution was heated atreflux for 30 minutes. After air-cooling, the solution was diluted with50 ml of water, and deposited solids were filtered off and washed withwater, ethanol and ether in this order to obtain 1.07 g of the subjectcompound (173) in a 97% yield.

Slightly yellowish powder:

Melting point: 192°-197° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.27 (t, J=7.0 Hz, 3H), 4.19 (q, J=7.0 Hz, 2H), 4.88(d, J=7.5 Hz, 2H), 7.77 (dd, J=7.0 Hz, 10.6 Hz, 1H), 7.98 (t, J=7.5 Hz,1H), 8.68 (s, 1H)

EXAMPLE 51

Ethyl3,4-Difluoro-1,2-dihydro-1-hydroxymethyl-6-oxo-1H,6H-pyrido[3,2,1-hi]indazole-7-carboxylate(174):

1.07 g (3.9 mmol) of the compound (173) obtained in Example 50 was addedto a mixture solution of 20 ml of formic acid and 10 ml of 37%formaldehyde solution, and the solution was heated at reflux for 2hours. After air-cooling, the solution was diluted with 50 ml of water,and deposited crystals were filtered off and washed with water, cooledethanol and ether in this order to obtain 1.14 g of the subject compound(174) in a 96% yield.

Colorless needles:

Melting point: 194°-201° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.0 Hz, 3H), 4.22 (q, J=7.0 Hz, 2H), 4.71(d, J=7.0 Hz, 2H), 4.93 (s, 2H), 6.26 (t, J=7.0 Hz, 1H), 7.75 (dd, J=7.0Hz, 10.6 Hz, 1H), 8.83 (s, 1H)

EXAMPLE 52

3,4-Difluoro-1,2-dihydro-1-hydroxymethyl-6-oxo-1H,6H-pyrido[3,2,1-hilindazole-7-carboxylicacid (175):

61 mg (0.2 mmol) of the compound (174) obtained in Example 51 was addedto a mixture solution of 1 ml of formic acid and 1 ml of water, and thesolution was heated at reflux for 6 hours. After air-cooling, thesolution was diluted with 50 ml of water, and deposited crystals werefiltered off and washed with water, ethanol and ether in this order toobtain 41 mg of the subject compound (175) in a 73% yield.

Colorless needles:

Melting point: 265°-277° C. (decomp.)

¹ H-NMR (DMSO-d₆): 4.85 (d, J=7.0 Hz, 2H), 5.04 (s, 2H), 6.31 (t, J=7.0Hz, 1H), 8.02 (dd, J=7.0 Hz, 10.6 Hz, 1H), 9.30 (s, 1H)

EXAMPLE 53

Ethyl3,4-Difluoro-1,2-dihydro-1-methoxymethyl-6-oxo-1H,6H-pyrido[3,2,1-hi]indazole-7-carboxylate(176):

61 mg (0.2 mmol) of the compound (175) obtained in Example 52 was addedto 2 ml of dimethylsulfate, and the solution was stirred at 120° C. for6 hours. After air-cooling, the content was added to 50 ml of saturatedaqueous sodium carbonate solution, and the solution was stirred for 4hours at room temperature. The solution was extracted with chloroform,and after the extract was dried over magnesium sulfate, the solvent wasremoved under reduced pressure by distillation. The solid residue wasdispersed in ether, and the precipitate was filtered off and washed withether to obtain 57 mg of the subject compound (176) in a 89% yield.

Yellowish powder:

Melting point: 183°-199° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.0 Hz, 3H), 3.34 (s, 3H), 4.24 (q, J=7.0Hz, 2H), 4.67 (s, 2H), 4.98 (s, 2H), 7.79 (dd, J=7.0 Hz, 10.6 Hz, 1H),8.88 (s, 1H)

EXAMPLE 54

Ethyl4,5-Difluoro-1-hydroxymethyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylate(177):

100 mg of the compound (5) obtained in Example 1 was dissolved in 3 mlof acetic acid, and while stirring, 1.5 ml of formalin was added to thesolution. The solution was stirred for 30 minutes, and the depositedsolid matter was filtered off and washed with ether to obtain 64 mg ofthe subject compound (177).

Colorless needles:

Melting point: >245 ° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.27 (t, J=7.0 Hz, 3H), 3.01 (brs, 2H), 3.63 (t,J=6.4 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H), 4.50 (d, J=6.3 Hz, 2H), 6.20 (t,J=6.3 Hz, 1H), 7.92 (dd, J=8.8 Hz, 10.7 Hz, 1H), 8.48 (s, 1H)

EXAMPLE 55

4,5-Difluoro-1-hydroxymethyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (178):

50 mg of compound (10) obtained in Example 3(4) was suspended in 3 ml ofacetic acid, and while stirring, 1.5 ml of formalin was added to thesolution. The solution was stirred for 1 hour, and ether was added tothe solution. The deposited solid matter was filtered off and washedwith ether to obtain 40 mg of the subject compound (178).

Colorless needles:

Melting point: >255° C. (decomp.)

¹ H-NMR (DMSO-d₆): 3.01 (brs, 2H), 3.69 (t, J=5.9 Hz, 2H), 4.57 (d,J=7.0 Hz, 2H), 6.22 (t, J=7.0 Hz, 1H), 8.17 (dd, J=8.8 Hz, 10.3 Hz, 1H),8.77 (s, 1H)

EXAMPLE 56

5-Fluoro-4-(pyrrolidin-1-yl)-1-hydroxymethyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (179):

200 mg of the compound (160) obtained in Example 38 was added to amixture solvent of 8 ml of acetic acid and 4 ml of formalin, and thesolution was heated at 80° C. for 2 hours. The deposited solid matterwas filtered off and washed with ether to obtain 50 mg of the subjectcompound (179).

Yellowish powder:

Melting point: 258°-261° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.51 (brs, 2H), 2.90 (t, J=5.9 Hz, 2H), 3.24-3.72 (m,6H), 4.55 (d, J=6.8 Hz, 2H), 6.25 (t, J=6.8 Hz, 1H), 7.82 (d, J=14.2 Hz,1H), 8.62 (s, 1H)

EXAMPLE 57

Ethyl4,5-Difluoro-1-methoxymethyl-2,3-dihydro-7-oxo-1H,7H-Pyrido[3,2,1-il]cinnoline-8-carboxylate(180):

65 mg of the compound (177) obtained in Example 54 was suspended in 5 mlof tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride wasadded to the solution. The solution was stirred for 4 hours, and 1 ml ofmethanol was added to the solution. The deposited solid matter wasfiltered off and washed with ether to obtain 34 mg of the subjectcompound (180).

Colorless needles:

Melting point: >240° C. (decomp.)

¹ H-NMR (CDCl₃): 1.41 (t, J=7.0 Hz, 3H), 3.05 (t, J=5.9 Hz, 2H), 3.36(s, 3H), 3.63 (t, J=6.4 Hz, 2H), 4.35-4.42 (m, 4H), 8.13 (dd, J=8.8 Hz,10.3 Hz, 1H), 8.50 (s, 1H)

EXAMPLE 58

Ethyl4,5-Difluoro-1-ethoxymethyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(181):

65 mg of the compound (177) obtained in Example 54 was suspended in 5 mlof tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride wasadded to the solution. The solution was stirred for 4 hours, and 1 ml ofethanol was added to the solution. The deposited solid matter wasfiltered off and washed with ether to obtain 28 mg of the subjectcompound (181).

Colorless powder:

Melting point: >190° C. (decomp. )

¹ H-NMR (CDCl₃): 1.11 (t, J=7.3 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H), 3.05(t, J=5.9 Hz, 2H), 3.55 (q, J=7.3 Hz, 2H), 3.64 (t, J=6.4 Hz, 2H),4.34-4.46 (m, 4H), 8.13 (dd, J=8.8 Hz, 10.3 Hz, 1H), 8.50 (s, 1H)

EXAMPLE 59

4,5-Difluoro-1-benzyl-2,3-dihydro-7-oxo-1H,7H-pyrido-[3,2,1-il]cinnoline-8-carboxylicacid (182):

530 mg of compound (10) obtained in Example 3(4) was added to 15 ml oftoluene, and then 1 ml of benzyl alcohol and 456 mg of p-toluenesufonicacid monohydrate were added to the solution. While the produced waterwas removed, the solution was heated at 130° C. for 48 hours. Thesolvent was removed by distillation. To the residue, ether was added,and the solid matter was filtered off and washed with ether to obtain370 mg of the subject compound (182).

Slightly yellowish needles:

Melting point: >194° C. (decomp.)

¹ H-NMR (CDCl₃): 3.18 (t, J=5.9 Hz, 2H), 3.59 (t, J=6.4 Hz, 2H), 4.11(s, 2H), 7.27-7.40 (m, 5H), 8.20 (dd, J=8.8 Hz, 9.8 Hz, 1H), 8.49 (s,1H)

EXAMPLE 60

5-Fluoro-4-(pyrrolidin-1-yl)-1-benzyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (183):

50 mg of compound (182) obtained in Example 59, 26 mg of pyrrolidine and10 mg of triethylamine were added to 3 ml of acetonitrile, and thesolution was heated at 80° C. for 3 hours. The solvent was removed bydistillation. To the residue, ethanol was added, and the solid matterwas filtered off and washed with ethanol and ether in this order toobtain 33 mg of the subject compound (183).

Slightly yellowish needles:

Melting point: 174°-180° C.

¹ H-NMR (CDCl₃): 2.04 (brs, 4H), 2.97 (t, J=5.9 Hz, 2H), 3.46 (t, J=6.4Hz, 2H), 3.58 (brs, 4H), 4.16 (s, 2H), 7.26-7.39 (m, 5H), 7.99 (d,J=13.7 Hz, 1H), 8.46 (s, 1H)

EXAMPLE 61

4-(2-Aminoethylthio)-5-fluoro-1-methyl-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (184):

100 mg of compound (8) obtained in Example 3(1), 56 mg of2-amino-ethanethiol and 109 mg of triethylamine were added to 2 ml ofacetonitrile, and the solution was heated at reflux for 2 hours. Afterair-cooling, the solvent was removed by distillation. To the residue,ethanol was added, and the deposited solids were filtered off and washedwith ether to obtain 60 mg of the subject compound (184).

Colorless powder:

Melting point: >200° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.68 (t, J=6.4 Hz, 2H), 2.87 (s, 3H), 3.07 (t, J=6.8Hz, 2H), 3.22-3.30, 3.51-3.62(each m, each 2H), 7.99 (d, J=9.8 Hz, 1H),8.79 (s, 1H)

REFERENCE EXAMPLE 28

3-Fluoro-2-(2-hydoxyethyl)nitrobenzene (185):

While cooling on ice, 6.52 g (94.5 mmol) of sodium nitrite was added to45 ml of concentrated sulfuric acid through 30 minutes. Then, 180 ml ofacetic acid solution containing 14.5 g (72.9 mmol) of the compound (124)obtained in Reference Example 6 was dropped to the solution through 1.5hours below 20° C. The solution was stirred for 20 minutes. The solutionwas dropped to 300 ml ethanol suspension containing 40.9 g (285.8 mmol)of cuprous oxide. The reaction solution was heated at 50° C. and wasstirred for 20 minutes. The solution was added to 1.0 1 of ice/water,and 1.0 l of chloroform was added to the solution. The insoluble matterwas filtered off, and the organic layer was separated. After drying overmagnesium sulfate, the solvent was removed by distillation, and theresidue was separated by column chromatography (silica gel 500 g, eluentsolvent; chloroform) to obtain 6.22 g of the subject compound (185) in a46% yield.

REFERENCE EXAMPLE 29

Diethyl {3-Fluoro-2-(2-hydroxyethyl)anilino}-methylene malonate (186):

15.4 g of iron powder and 1.4 ml of concentrated hydrochloric acid wereadded to a mixture solvent of 160 ml of water and 30 ml of ethanol, andthe solution was heated at 80°-90° C. 20.3 g (110 mmol) of the compound(185) obtained above was added to the solution through 15 minutes, andthe solution was heated for 10 minutes. After air-cooling, 200 ml ofethyl acetate was added to the solution, and insoluble matter wasfiltered. The organic layer was separated and was washed with aqueous10% sodium hydrogen carbonate solution. After drying over magnesiumsulfate, the solvent was removed by distillation. To the obtained oilymaterial, 23.2 g (107 mmol) of diethyl ethoxymethylenemalonate wasadded, and the solution was heated at 120° C. for 4 hours. Afterair-cooling, crystals were dispersed in n-hexane and filtered off toobtain 21.9 g of the subject compound (186) in a 61% yield.

REFERENCE EXAMPLE 30

Ethyl 7-Fluoro-8-(2-hydroxyethyl)-4-hydroxyquinoline-3-carboxylate(187):

To 120 ml of methylene chloride solution containing 20.0 g (61.7 mmol)of compound (186) obtained above and 5.11 g (75 mmol) of imidazole, 25ml of methylene chloride solution containing 11.2 g (74.4 mmol) oft-butyldimethylchlorosilane was dropped through 5 minutes, and thesolution was stirred for 40 minutes at room temperature. The solutionwas washed with 50 ml of water, and after drying over magnesium sulfate,the solvent was removed by distillation. To the obtained oily material,210 ml of Dowtherm A (Trademark) was added, and the solution was heateduntil a fraction of 200° C. was taken off. The solution was furtherheated at reflux for 20 minutes. After air-cooling, 30 ml ofconcentrated hydrochloric acid was added to the solution. After stirringfor 20 minutes at room temperature, the solution was neutralized withsodium hydrogen carbonate. The deposited crystals were filtered off andwashed with water, ethanol and ether in this order to obtain 8.99 g ofthe subject compound (187) in a 52% yield.

REFERENCE EXAMPLE 31

Ethyl1-Amino-7-fluoro-8-(2-hydroxyethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate(188):

8.99 g (32.2 mmol) of the compound (187) obtained above and 8.89 g (64.4mmol) of anhydrous potassium carbonate were added to 210 ml ofN,N-dimethylformamide, and the solution was stirred at room temperaturefor 4 hours. 27.6 g (96.7 mmol) of ethylo-(mesitylenesulfonyl)acetohydoxamate was added to 40 ml of dioxane, andwhile cooling on ice, 10.5 ml of 70% perchloric acid was dropped to thesolution below 10° C. over 30 minutes. The solution was stirred for 20minutes, and was then added to 400 ml of ice/water. Crystals werefiltered off and washed on ice/water and was dissolved in 150 ml ofmethylene chloride. The organic layer was separated and after dryingover magnesium sulfate, while cooling on ice, the solution was droppedinto the previously prepared reaction solution of N,N-dimethylformamidethrough 10 minutes. The solution was stirred for 1 hour, and 200 ml ofwater was added to the solution. Crystals were filtered off and washedwith water, ethanol and ether in this order to obtain 1.81 g of thesubject compound (188) in a 19% yield.

EXAMPLE 62

Ethyl4-Fluoro-2,3-dihydro-7-oxo-1H,7H-pyrido-[3,2,1-il]cinnoline-8-carboxylate(189):

1.81 g (6.2 mmol) of the compound (188) obtained in Reference Example 31and 2.55 (9.7 mmol) of triphenylphosphine were added to 40 ml oftetrahydrofuran, and 40 ml of tetrahydrofuran solution containing 1.69(9.7 mmol) of diethyl azodicarboxylate was dropped to the solution atroom temperature through 1.5 hours. After 30 minutes, the solvent wasremoved by distillation. Solids were dispersed in ethanol, filtered offand washed with ethanol and ether in this order to obtain 1.24 g of thesubject compound (189) in a 72% yield.

Colorless powder:

Melting point: 224°-225° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.27 (t, J=6.9 Hz, 3H), 2.88 (brs, 2H), 3.39 (brs,2H), 4.20 (q, J=7.0 Hz, 2H), 6.85 (brs, 1H), 7.34 (dd, J=8.8 Hz, 8.8 Hz,1H), 8.09 (dd, J=6.6 Hz, 6.6 Hz, 1H), 8.42 (s, 1H)

EXAMPLE 63

Methyl4-Fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(190):

To 1.24 g (4.5 mmol) of the compound (189) obtained in Example 62, 8 ml(87 mmol) of dimethylsulfate was added, and the solution was heated at120° C. for 3 hours. After air-cooling, the solution was added to 70 mlof ice/water to which 12 g (87 mmol) of anhydrous potassium carbonatewas added, and the solution was stirred for 1 hour. The solution wasextracted with 100 ml of chloroform, and after drying over magnesiumsulfate, the solvent was removed by distillation. The residue wasseparated by column chromatography (silica gel 40g, eluent solvent;chloroform:methanol=100:1) to obtain 571 mg of the subject compound(190) in a 46% yield.

Colorless powder:

Melting point: 199°-203° C. (decomp.)

¹ H-NMR (CDCl₃): 2.87 (s, 3H), 3.04 (t, J=5.9 Hz, 2H), 3.50 (t, J=5.9Hz, 2H), 3.92 (s, 3H), 7.15 (dd, J=8.4 Hz, 8.4 Hz, 1H), 8.35 (dd, J=6.2Hz, 9.0 Hz, 1H), 8.59 (s, 1H)

EXAMPLE 64

4-Fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido-[3,2,1-il]cinnoline-8-carboxylicacid (191):

To 40 mg (0.14 mmol) of the compound (190) obtained in Example 63, 0.3ml of concentrated hydrochloric acid and 1.2 ml of acetic acid wereadded, and the solution was heated at reflux for 3 hours. Afterair-cooling, 5 ml of water was added to the solution, and depositedcrystals were filtered off and washed with water, ethanol and ether inthis order to obtain 30 mg of the subject compound (191) in a 79% yield.

Colorless needles:

Melting point: 213° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.89 (s, 3H), 3.07 (t, J=5.9 Hz, 2H), 3.53 (t, J=6.2Hz, 2H), 7.59 (dd, J=8.8 Hz, 8.8 Hz, 1H), 8.32 (dd, J=6.9 Hz, 9.2 Hz,1H), 8.81 (s, 1H)

EXAMPLE 65

4-(Pyrrolidin-1-yl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (192):

15 mg (0.06 mmol) of the compound (191) obtained in Example 64 and 0.1ml of pyrrolidine were added to 5 ml of acetonitrile, and the solutionwas heated at reflux for 2 hours. After the solvent was removed bydistillation, obtained crystals were dispersed in ethanol and filteredoff and washed with ethanol and ether in this order to obtain 15 mg ofthe subject compound (192) in a 84% yield.

Slightly yellowish prisms:

Melting point: 272° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.94 (brs, 4H), 2.92 (s, 3H), 3.01 (brs, 2H), 3.54(brs, 4H), 7.15 (d, J=10.6 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.60 (s, 1H)

REFERENCE EXAMPLE 32

Ethyl1-(N-t-Butyloxycarbonyl-N-methylamino)-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(193):

A mixture of 28.6 g ethyl 2,3,4,5,6-pentafluorobenzoyl acetate, 23.2 gof ethyl orthoformate and 32.3 g of acetic anhydride was heated atreflux for 8 hours. The solvent was removed by distillation. Theobtained oily material was dissolved in 100 ml of methylene chloride,and while cooling on ice, 30 ml of methylene chloride solutioncontaining 14.6 g N-(t-butyloxycarbonyl)-N-methyl-hydrazine was droppedto the solution. The solution was stirred for 2 hours, and the solventwas removed by distillation. The obtained oily material was crystallizedfrom n-hexane, and crystals were filtered off to obtain 18.2 g of ethyl2-(2,3,4,5,6,-pentafluorobenzoyl)-3-(2-t-butyloxycarbonyl-2-methylhydrazino)acrylate.

The obtained ethyl acrylate and 6.2 g of anhydrous potassium carbonatewere added to 50 ml of N,N-dimethylformamide, and the solution washeated at 70° C. for 1 hour. The reaction solution was added to 200 mlof ice/water, and the precipitate was filtered off. The precipitate wasdissolved in 200 ml of chloroform, and the solution was washed withwater. After drying over magnesium sulfate, the solvent was removed bydistillation. The obtained oily material was crystallized from n-hexaneto obtain 13.7 g of the subject compound (193) in a 33% yield.

REFERENCE EXAMPLE 33

Ethyl1-(N-Methylamino)-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(194):

4.2 g of the compound (193) obtained above was dissolved in 30 ml ofethyl acetate, and while cooling with ice, 40 ml of 4N hydrochloric acidsolution in dioxane was added to the solution. The solution was stirredovernight at room temperature, and the solvent was removed bydistillation. The residue was dissolved in 100 ml of chloroform, and 50ml of aqueous 10% sodium carbonate solution was added to the solution.The solution was stirred for 30 minutes at room temperature. The organiclayer was separated and after drying over magnesium sulfate, the solventwas removed by distillation. Crystals were dispersed in ether andfiltered to obtain 2.9 g of the subject compound (194) in a 91% yield.

EXAMPLE 66

Ethyl1-[N{2,2-Bis-(t-butyloxycarbonyl)ethyl}-N-methyl]-amino-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(195):

9.5 g of the compound (194) obtained above and 13.7 g of di-t-butylmethylenemalonate were added to 90 ml of methylene chloride, and whilecooling on ice, 3.3 ml of titanium tetrachloride was dropped to thesolution through 40 minutes. The solution was further stirred for 1hour. The reaction solution was poured into ice/water, and the organiclayer was separated. After drying over magnesium sulfate, the solventwas removed by distillation. The obtained oily material was separated bycolumn chromatography (silica gel, eluent solvent; ethylacetate:methylene chloride=1:20) to obtain 8.6 g of the subject compound(195) in a 47% yield.

Colorless powder:

Melting point: 118°-122° C.

¹ H-NMR (CDC₃): 1.39 (s,12H), 1.46 (s, 9H), 3.00 (s, 3H), 3.19-3.23 (m,1H), 3.48-3.62 (m, 2H), 4.40 (q, J=7.1 Hz, 2H), 8.52 (s, 1H)

EXAMPLE 67

Ethyl3,3-Bis-(t-butyloxycarbonyl)-4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(196):

10.0 g of the compound (195) obtained in Example 66 was dissolved in 150ml of dimethylsulfoxide, and the solution was stirred at roomtemperature. 3.0 g of cesium carbonate was added to the solution, andthe solution was stirred at 80° C. for 3 hours. After air-cooling, thereaction solution was added to 500 ml of aqueous 5% citric acid solutionand 500 ml of ethyl acetate, and the organic layer was separated fromthe solution. After drying over magnesium sulfate, the solvent wasremoved by distillation. The residue was dissolved in ether, andinsoluble matter was filtered. The filtrate was removed by distillation,and the residue was separated by column chromatography (silica gel,eluent solvent; chloroform) to obtain 1.6 g of the subject compound(196) in a 17% yield.

Colorless powder:

Melting point: 169°-173° C.

1H-NMR (CDC₃): 1.40 (t, J=7.1 Hz, 3H), 1.49 (s, 18H), 2.76 (s, 3H), 4.04(s, 2H), 4.39 (q, J=7.1 Hz, 2H), 8.47 (s, 1H)

EXAMPLE 68

4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-8-ethoxycarbonyl-1H,7H-pyrido[3,2,1-ij]cinnoline-3-carboxylicacid (197):

1.0 g of the compound (196) obtained in Example 67 was dissolved in 2 mlof trifluoroacetic acid, and the solution was heated at 60° C. for 2hours. The reaction solution was added to 50 ml of isopropyl ether, anddeposited solids were filtered off to obtain 0.67 g of the subjectcompound (197) in a 99% yield.

Colorless powder:

Melting point: 219°-223° C. (decomp.)

¹ H-NMR (DMSO-d₆): 1.28 (t, J=7.1 Hz, 3H), 2.78 (s, 3H) 3.73-3.76 (m,2H), 4.18-4.25 (m, 3H), 8.45 (s, 1H)

EXAMPLE 69

Ethyl4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylate(198):

300 mg of the compound (197) obtained in Example 68 was dissolved in 6ml of N-methylpyrrolidone, and the solution was heated at 160° C. for 3hours. After air-cooling, the water was added to the reaction solution,and the solution was extracted with chloroform three times. After dryingover magnesium sulfate, the solvent was removed by distillation. Theresidue was separated by column chromatography (silica gel, eluentsolvent; chloroform) to obtain 128 mg of the subject compound (198) in a49% yield.

Colorless powder:

Melting point: 236°-240° C.

¹ H-NMR (CDCl₃): 1.40 (t, J=7.1 Hz, 3H), 2.83 (s, 3H), 3.00-3.08,3.44-3.51 (each m, each 2H), 4.38 (q, J=7.1 Hz, 2H), 8.49 (s, 1H)

EXAMPLE 70

4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (199):

30 mg of the compound (198) obtained in Example 69 was added to 0.4 mlof acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solutionwas heated at 100° C. for 2 hours. After air-cooling, water was added tothe reaction solution, and deposited solids were filtered off and washedwith water, ethanol and ether in this order to obtain 22 mg of thesubject compound (199) in a 81% yield.

Colorless powder:

Melting point: 255°-260° C. (decomp.)

¹ H-NMR (DMSO-d₆): 2.85 (s, 3H), 3.07-3.10, 3.49-3.55 (each m, each 2H),8.78 (s, 1H)

EXAMPLE 71

Ethyl4,5-Difluoro-6-benzylamino-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylate(200):

62 mg of the compound (198) obtained in Example 69 and 50 mg ofbenzylamine were added to 2 ml of toluene, and the solution was heatedat 80° C. for 24 hours. The reaction solution was added to chloroformand was washed with aqueous 5% citric acid solution. After drying overmagnesium sulfate, the solvent was removed by distillation. Obtainedsolids were dispersed in ether and filtered off to obtain 59 mg of thesubject compound (200) in a 74% yield.

Colorless powder:

Melting point: 186°-190° C.

¹ H-NMR (CDCl₃): 1.38 (t, J=7.3 Hz, 3H), 2.78 (s, 3H), 2.83-2.90,3.33-3.39 (each m, each 2H), 4.36 (q, J=7.3 Hz, 2H), 4.68, 4.70 (each d,each J=3.9 Hz, each 1H), 7.22-7.38 (m, 5H), 8.40 (s, 1H), 10.81 (brs,1H)

EXAMPLE 72

Ethyl4,5-Difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H,7H-Pyrido[3,2,1-il]cinnoline-8-carboxylate(201):

59 mg of the compound (200) obtained in Example 71 was dissolved in 10ml of ethanol and 10 ml of acetic acid, and 5 mg of 10% palladium oncarbon was added to the solution. the solution was stirred for 24 hoursunder hydrogen. The catalyst was filtered, and the filtrate wasevaporated. The residue was dissolved in chloroform and was washed withsaturated aqueous sodium hydrogen-carbonate solution. After drying overmagnesium sulfate, the solvent was removed by distillation. Solids weredispersed in ether and filtered off to obtain 27 mg of the subjectcompound (201) in a 59% yield.

Yellowish powder:

Melting point: 255°-257° C.

¹ H-NMR (CDC₃): 1.39 (t, J=7.1 Hz, 3H), 2.80 (s, 3H), 2.89, 3.39 (eacht, each J=6.0 Hz, each 2H), 4.38 (q, J=7.1 Hz, 2H), 7.03 (brs, 2H), 8.44(s, 1H)

EXAMPLE 73

6-Amino-4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (202):

20 mg of the compound (201) obtained in Example 72 was added to 0.4 mlof acetic acid and 0.1 ml of 12 N hydrochloric acid, and the solutionwas heated at 100° C. for 2 hours. After air-cooling, the water wasadded to the reaction solution, and the deposited solids were filteredoff and washed consecutively with water, ethanol and ether to obtain 13mg of the subject compound (202) in a 72% yield.

Slightly yellowish powder:

Melting point: >290° C.

¹ H-NMR (DMSO-d₆): 2.80 (s, 3H), 2.86-2.91, 3.40-3.45 (each m, each 2H),7.71 (brs, 2H), 8.61 (s, 1H)

EXAMPLE 74

6-Amino-5-fluoro-4-(pyrrolidin-1-yl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid (203):

4 mg of the compound (202) obtained in Example 73 and 10 μl ofpyrrolidine were added to 1 ml of acetonitrile, and the solution washeated at 80° C. for 3 hours. After air-cooling, the solvent was removedby distillation, and the residue was filtered off and washed withethanol and ether in this order to obtain 2 mg of the subject compound(203).

Slightly yellowish powder:

Melting point: >290° C.

¹ H-NMR (CDCl₃): 1.97-2.06 (m, 4H), 2.79-2.85 (m, 2H), 2.86 (s, 3H),3.30-3.35 (m, 2H), 3.44-3.53 (m, 4H), 6.57 (brs, 2H), 8.66 (s, 1H)

EXAMPLE 75

5-Fluoro-4-(3-hydroxy-2-methylazetidin-1-yl)-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid (204):

Procedures of Example 61 were followed to obtain a title compound (204).

Slightly yellowish powder:

Melting point: 261°-263° C.

¹ H-NMR (DMSO-d₆): 1.41 (d, J=6.4 Hz, 3H), 2.87 (s, 3H), 3.82-3.97 (m,1H), 4.06 (brs, 1H), 4.52-4.70, 4.70-4.87 (each m, each 1H), 5.76 (brs,1H), 7.78 (d, J=14.7 Hz, 1H), 8.61 (s, 1H)

EXAMPLE 76

4-(3-Amino-2-methylazetidin-1-yl)-S-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxylicacid Hydro chloride (205):

Procedures of Example 61 were followed to obtain a title compound (205).

Yellowish powder:

Melting point: 205°-210° C.

¹ H-NMR (DMSO-d₆): 1.48 (d, J=6.0 Hz, 3H), 2.56-2.75 (m, 1H), 2.88 (s,3H), 3.00-3.22 (m, 1H), 3.72 (brs, 1H) 4.10-4.28, 4.75-4.90, 4.90-5.10(each m, each 1H), 7.81 (d, J=14.2 Hz, 1H), 8.63 (s, 1H), 8.70 (brs, 3H)

EXAMPLE 77

Ethyl8-Acetoxymethyl-1-(N,N-diacetylamino)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate(206):

680 mg(2 mmol) of compound(97) obtained in Example 14 was added to 10 mlof acetic anhydride, and the solution was heated at 110° C. for 4 hours.After air-cooling, the solvent was condensed under reduced pressure andtriturated with petroleum ether and filtered off. 776 mg of the titlecompound (206) was obtained. (yield 90%)

brown amorphous

¹ H-NMR(DMSO-d₆): 1.30(t, J=7.0 Hz, 3H), 2.00(s, 3H), 2.39(s, 6H), 4.28(q,J=7.0 Hz, 2H), 5.07(s, 2H), 8.30(dd, J=7.0 Hz, J=10.6 Hz,1H), 9.01(s,1H)

EXAMPLE 78

Ethyl8-Acetoxymethyl-1-(N-acetylamino)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate(207):

424 mg(l mmol) of compound(206) obtained in Example 77 was dissolved in10 ml of dimethylsulfoxide. 71 mg(l mmol) of pyrrolidine dissolved in 1ml of dimethylsulfoxide was added to the solution through 2 hours, whilestirring this solution at room temperature. After stirring at roomtemperature for 20 hours, 50 ml of water was added to the solution, andstirring was continued for 2 hours. Precipitated crystals were filtratedoff and washed with water and ether in this order. After drying invacuo, 353 mg of the title compound(207) was obtained. (yield 97%)

Slightly yellowish prisms

Melting point;119√-121 ° C.

¹ H-NMR(DMSO-d₆): 1.29(t, J=7.0 Hz, 3H), 2.03(s, 6H), 4.27(q, J=7.0 Hz,2H), 5.40(s, 2H), 8.22(dd, J=7.0 Hz, J=10.6 Hz, 1H), 8.59(s, 1H)

EXAMPLE 79

Ethyl8-Acetoxymethyl-1-(N-acetyl-N-methylamino)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate(208):

650 mg(l.7 mmol) of compound(207) obtained in Example 78 was dissolvedin 17ml of N,N-dimethylformamide, and then 510 mg of anhydrous potassiumcarbonate was added to the solution. 374 mg(2.55 mmol) of methyl iodidewas added to the solution while stirring at room temperare. Afterstirring at room temperature for 20 hours, 50ml of water was added tothe solution, and stirring was continued for 2 hours. Precipitatedcrystals were filtrated out and washed with water and ether in thisorder. After drying in vacuo 362 mg of the title compound (208) wasobtained.(yield 54%)

Slightly yellowish needles

Melting point; 196°-198 ° C.

1H-NMR(DMSO-d₆): 1.30(t, J=7.0 Hz, 3H), 1.72-2.23(m,6H), 3.34(s, 0.3H),3.56(s, 0.7H), 4.18-4.25(m, 2H), 4.87-5.39(m, 2H), 8.08-8.32(m, 1H),8.82(s, 0.7H), 8.95(s, 0.3H)

EXAMPLE 80

Ethyl(N-Methylamino)-6,7-difluoro-8-hydroxymethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylate(209):

793 mg(2 mmol) of compound(208) obtained in Example 79 was added tomixture solvent of 4 ml of ethanol and 8 ml of 4 N hydrochloricacidsolution in dioxane, and then the reaction mixture was heated at 60 ° C.for 5 hours. After air-cooling, an aqueous saturated sodium hydrogencarbonate solution was dropped to neutralize, while stirring at roomtemperature. Stirring was continued at room temperature for 2 hours.Precipitated crystals were filtrated out and washed with water and etherin this order. After drying in vacuo 506 mg of the title compound (209)was obtained.

Slightly yellowish needles

Melting point; 217°-222 ° C.

1H-NMR(DMSO-d₆): 1.30(t, J=7.0 Hz, 3H), 2.85(s, 3H), 3.37(s, 3H), 4.24(q,J=7.0 Hz, 2H), 5.02(brs, 2H), 5.11(brs, 1H),6.93 (m, 1H), 8.10(dd,J=7.0 Hz, J=10.6Hz, 111), 8.77(s, 1H)

EXAMPLE 81

Ethyl 3,4-Difluro-1,2-dihydro-1-methyl-6-oxo-1H,6H-pyrido[3,2,1-ij]-indazole-7-carboxylate(210):

437 mg(l.4 mmol) of compound(209) obtained in Example 80 was added to14ml of tetrahydrofuran. 283 mg(2.8 mmol) of triethylamine, 266 mg(1.4mmol) of p-toluenesulufonyl chloride and 10 mg of 4-(dimethylamino)pyridine were added to the reaction mixture, while stirring, and thenthe reaction mixture was heated at 60 ° C. for 6 hours. Afterair-cooling, Precipitated crystals were filtrated out and washed withtetrahydrofuran, water and tetrahydrofuran in this order. 257 mg of thetitle compound(210) was obtained. (yield 62%)

Colorless needles

Melting point; >215 ° C. (decomp.)

¹ H-NMR(DMSO-d₆): 1.28(t, J=7.0 Hz, 3H), 3.06(s, 3H), 4.21(q, J=7.0 Hz,2H), 4.87(s, 2H), 7.79(dd, J=7.0 Hz, J=11.4 Hz, 1H), 8.89(s, 1H)

EXAMPLE 82

3,4-Difluro-1,2-dihydro-1-methyl-6-oxo-1H,6H-pyrido[3,2,1-ij]indazole-7-carboxylicacid(211):

88 mg(O.3 mmol) of compound(210) obtained in Example 81 was added to amixture of 2 ml of formic acid and 2 ml of water, and the reactionmixture was heated at reflux for 6 hours. After air-cooling,Precipitated crystals were filtrated out and washed with water and etherin this order. After drying in vacuo 58 mg of the title compound (211)was obtained.(yield 73%)

Colorless needles

Melting point; >250 ° C. (decomp.)

¹ H-NMR(DMSO-d₆): 3.21(s, 3H), 4.99(s, 2H), 8.07(dd, J=7.0 Hz, J=11.1Hz, 1H), 9.27(s, 1H)

EXAMPLE 83

4-Fluoro-3-(pyrrolidin-1-yl)-1,2-dihydro-1-methyl-6-oxo-1H,6H-pyrido[3,2,1-hilindazole-7-carboxylicacid(212):

25 mg of compound(211) obtained in Example 82 and 21 mg of pyrrolidinein 0.6 ml of dimethylsulfoxide were stirred at room temperature for 1hour. The precipitated solid was filtered off and washed with ether andn-hexane succesively. Whereby, 18 mg of the title compound(212) wasobtained.

Yellowish powder

Melting point; >248° C. (decomp.)

¹ H-NMR(CDCl₃ /CD₃ OD=5/1): 2.03(brs, 4H), 3.12(s, 3H), 5.04(s, 2H),7.67(d, J=14.0 Hz, 1H), 8.70(s, 1H)

EXAMPLE 84

4-(7-Amino-5-azaspiro[2.4]heptan-5-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-il]cinnoline-8-carboxyicacid Hydrochloride(214):

Procedure of Example 6(1) were followed to obtaine the titlecompound(214).

Yellowish powder

Melting point; 222°-225° C. (decomp.)

¹ H-NMR(DMSO-d₆): 0.75(brs, 2H), 0.87-0.95(m, 1H), 1.12-1.22(m, 1H),2.90(s, 3H), 3.04-3.19(m, 3H), 4.07(d, J=9.5 Hz, 1H), 4.14-4.25(m, 1H),7.89(d, J=13.9 Hz, 1H), 8.43(brs, 2H), 8.71(s, 1H)

What is claimed is:
 1. A tricyclic compound represented by Formula I ora pharmaceutically acceptable salt thereof, ##STR124## wherein n is 1,R¹ is hydrogen, lower alkyl, benzyl, phenyl, lower alkanoyloxy-loweralkyl, lower alkoxycarbonyloxy-lower alkyl, lower alkoxymethyl,phthalidyl, di-lower alkyl amino-lower alkyl or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl;R² is hydrogen, halogen, oramino group which may be substituted by benzylidene,hydroxy-benzylidene, mono-, di-, or tri-phenyl(lower)alkyl or an acylgroup selected from lower alkanoyl, mono-, di- or tri-halo(loweralkanoyl, lower-alkoxycarbonyl, carbamoyl, benzoyl, toluoyl, naphthoyl,phenyl(lower)alkanoyl, phenyloxycarbonyl, naphthyloxycarbonyl,phenoxy(lower)alkanoyl, phenylglyoxyloyl, naphthylglyoxyloyl,benzyloxycarbonyl and p-nitrobenzyloxycarbonyl; R³ is hydrogen or loweralkyl; R⁴ is hydrogen, lower alkyl which may be substituted by hydroxyl,halogen or lower alkoxy; phenyl-lower alkyl, or an acyl group selectedfrom lower alkanoyl, lower-alkoxycarbonyl, benzoyl, phenyloxycarbonyl; Xis hydrogen or halogen; Y is pyrrolidinyl group which may beunsubstituted or either mono- or di-substituted with a substituentselected from the group consisting of a halogen atom, a hydroxyl group,an amino group, an amino-lower alkyl group and a lower alkyl group, or Yis a group represented by Formula R⁵ --(CH₂)_(m) --A-- wherein R⁵ ishydrogen or lower cycloalkyl which may be substituted by amino; m is aninteger from 0 to 3 and A is oxygen or sulfur.
 2. The compound of claim1, wherein R¹, R² and R³ are hydrogen, R⁴ is methyl, X is a halogen atomand Y is a pyrrolidinyl group either mono- or di-substituted with asubstituent selected from the group consisting of a halogen atom, ahydroxyl group, an amino group, an amino-lower alkyl group and a loweralkyl group.
 3. The compound of claim 1 wherein the tricyclic compoundis4-(cis(-)3-amino-4-methylpyrrolidin-1-yl)-5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylicacid.
 4. The compound of claim 1 wherein R¹, R² and R³ are hydrogen, R⁴is methyl, X is halogen and Y is a group represented by a Formula R⁵--(CH₂)_(m) --A-- wherein R⁵ is hydrogen or lower cyclo alkyl which maybe substituted by amino, m is an integer from 0 to 3 and A is oxygen orsulfur.